Smoking Cessation in the ITALUNG Lung Cancer Screening: What Does "Teachable Moment" Mean?

BACKGROUND: Changes in smoking habits and predictors of smoking cessation were examined in the randomized ITALUNG lung cancer screening trial. METHODS: In three centers, eligible smokers or ex-smokers (55-69 years, ≥20 pack-years in the last 10 years) were randomized to receive annual invitation for low-dose computed tomography for 4 years or usual care. At invitation, subjects received written information for a free smoking cessation program. Quitting outcome was assessed at year 4. RESULTS: Among participants who completed baseline assessments and year 4 screening, higher quitting (20.8% vs. 16.7%, p = .029) and lower relapse (6.41% vs. 7.56%, p = .50) rates were observed in the active screening group as compared to the usual-care control group. Corresponding figures in the intention-to-treat analysis were as follows: 16.04% versus 14.64% (p = .059) and 4.88% versus 6.43% (p = .26). Quitting smoking was significantly associated to male gender, lower pack-years, and having pulmonary nodules at baseline. Center-specific analyses showed a threefold statistically significant higher probability to quit associated with participating in the smoking cessation program. A subsample of smokers of the scan group from one center showed higher quitting rates over 12-month follow-up as compared to matched controls from the general population who underwent the same smoking cessation program. CONCLUSIONS: Consistently with previous reports, in the ITALUNG trial, screened subjects showed significantly higher quit rates than controls, and higher quit rates were associated with both the presence of pulmonary nodules and participating in a smoking cessation program. Maximal effect on quitting outcome was observed with the participation in the smoking cessation program. IMPLICATIONS: Participating in lung cancer screening promotes smoking cessation. An effective "teachable moment" may be achieved when the smoking cessation intervention is structured as integral part of the screening clinical visits and conducted by a dedicated team of health care professionals. Standardized guidelines for smoking cessation interventions in lung cancer screening are needed.

Mortality, survival and incidence rates in the ITALUNG randomised lung cancer screening trial.

BACKGROUND: ITALUNG is contributing to the European evaluation of low-dose CT (LDCT) screening for lung cancer (LC). METHODS: Eligible subjects aged 55-69 years, smokers or ex-smokers (at least 20 pack-years in the last 10 years), were randomised to receive an annual invitation for LDCT screening for 4 years (active group) or to usual care (control group). All participants were followed up for vital status and cause of death (at the end of 2014) and LC incidence (at the end of 2013). Pathological and clinical information was collected from the Tuscan Cancer Registry data. RESULTS: 1613 subjects were randomly assigned to the active group and 1593 to the control group. At the end of the follow-up period 67 LC cases were diagnosed in the active group and 71 in the control group (rate ratio (RR)=0.93; 95% CI 0.67 to 1.30). A greater proportion of stage I LC was observed in the active group (36% vs 11%, p<0.001). Non-significant reductions of 17% (RR=0.83; 95% CI 0.67 to 1.03) for overall mortality and 30% (RR=0.70; 95% CI 0.47 to 1.03) for LC-specific mortality were estimated. CONCLUSIONS: Despite the lack of statistical significance, the ITALUNG trial outcomes suggest that LDCT screening could reduce LC and overall mortality. Moreover, the comparison of the number of LC cases diagnosed in the two groups does not show overdiagnosis after an adequate follow-up period. A pooled analysis of all European screening trials is advocated to assess the benefit-to-harm ratio of LDCT screening and its implementation in public health settings. TRIAL REGISTRATION NUMBER: Results, NCT02777996.

Idiopathic interstitial pneumonias: do HRCT criteria established by ATS/ERS/JRS/ALAT in 2011 predict disease progression and prognosis?

PURPOSE: The objective of the study was to determine whether HRCT criteria for Usual Interstitial Pneumonia (UIP), possible UIP or no-UIP pattern recommended by ATS/ERS/JRS/ALAT guidelines 2011 are able to predict progression and prognosis of the disease in a group of patients with fibrotic idiopathic interstitial pneumonia (IIP). MATERIALS AND METHODS: This was a retrospective study conducted with the approval of the ethics committee. Two radiologists at baseline HRCT distributed 70 patients with fibrotic IIP into three groups on the basis of the 2011 guidelines: UIP pattern (group 1), possible UIP pattern (group 2), inconsistent with UIP pattern (group 3). The different abnormalities (honeycombing, reticulation, ground-glass and traction bronchiectasis), fibrotic score (reticulation + honeycombing) and overall CT score were visually scored at baseline and during the follow-up (total HRCT 178). The mortality rate of the three groups was compared. The baseline abnormalities were then correlated with the mortality rate in the UIP group. RESULTS: The inter-observer agreement in the classification of the abnormalities in the three groups was almost perfect (k = 0.92). After consensus, 44 patients were classified into group 1, 13 into group 2 and 13 into group 3. During a mean follow-up of 1386 days, overall CT score, fibrotic score, honeycombing and traction bronchiectasis showed a significant progression in group 1. The mortality rate was significantly higher in group 1 (18 deaths) versus group 2 and 3 (1 death each). In group 1, baseline honeycombing rate higher than 25 %, fibrotic score higher than 30, overall CT score greater than 45 and traction bronchiectasis in more than 4 lobes defined the worst prognosis. CONCLUSION: HRCT classification based on 2011 guidelines showed high accuracy in stratifying fibrotic changes because in our study UIP, possible UIP and inconsistent with UIP pattern seem to be correlated with different disease progression and mortality rate.

[Tobacco farming in Italy receives more funds in comparison to tobacco control]. / La tabacchicoltura in Italia riceve più fondi del controllo del tabagismo.

In the European Union almost 300,000 tons of raw tobacco are produced every year, contributing for 4% of the world production. In Italy, tobacco crop produces around 90,000 tons/year and is concentrated in Veneto, Tuscany, Umbria and Campania Regions. In 1970, Common Market Organisation provided a virtually unlimited support for European tobacco production. After 2004, funds progressively has been cut by half, even though the other half has been given for restructuring or reconversion of tobacco farms through the Rural Development Plan. The Framework Convention on Tobacco Control recommends conversion of tobacco crops, although there are no effective measures. Tobacco production requires large quantities of chemicals (pesticides, growth regulators, fertilisers), with significant workers' exposure if applied without personal protective equipments. Pesticides may have genotoxic, teratogenic, immunotoxic, hormonal, and carcinogenic effects. Tobacco itself may cause also a disease called "Green tobacco sickness" syndrome, as a consequence of nicotine dermal absorption due to skin exposure to tobacco leaves. In Italy, financial resources for tobacco production and restructuring/conversion to other crops of previously tobacco planted fields are available. On the contrary, anti-smoking media interventions do not receive funds comparatively relevant as those for tobacco production.

[Cigarette smoking in pregnancy: observational prospective study in three towns of Tuscany Region (Central Italy)]. / Fumo di sigaretta in gravidanza: studio osservazionale prospettico in tre città della Toscana.

OBJECTIVE: to assess the prevalence of smoking in pregnancy and its changes after childbirth, and the characteristics associated with a greater likelihood of smoking during pregnancy in a sample of women attending three university hospitals in Tuscany (Central Italy). DESIGN: observational prospective multicentric study. SETTING AND PARTICIPANTS: 1,036 women in ninth month of pregnancy were enrolled at the teaching hospitals of Careggi (Firenze), Pisa and Siena. Women filled a standardized, self-administered questionnaire at enrolment. A second questionnaire was administered by phone to the smoking, ex-smoking and abstinent-during-pregnancy women one year after the delivery. RESULTS: 60.5% of women was never smoker, 17.4% was ex-smoker, 14% of women stopped smoking during pregnancy, and 8.4% were current smokers. Smoking in pregnancy was significantly associated with being younger than 31 years old (OR 1.75; 95%CI 1.01-1.84) and unmarried (OR 1.75; 95%CI 1.10- 2.78), having a low school degree (OR 2.31; 95%CI 1.58-3.36) and a smoking partner (OR 3.03; 95%CI 2.32-3.96). The absolute risk of smoking during pregnancy was 42%. One year after delivery, 44%of women who stopped smoking in pregnancy relapsed. CONCLUSIONS: a not negligible percentage of women residents in Tuscany Region smokes during pregnancy. Relapses after delivery are high. Even if recently in Italy a smoke free legislation was implemented, the study shows a low attention toward passive smoking during pregnancy. Smoking cessation interventions specifically tailored for pregnant women and relapses prevention need to be implemented in Tuscany by all health care professionals who care for women during pregnancy and after delivery.

Pleural Effusion in COVID-19 Pneumonia: Clinical and Prognostic Implications-An Observational, Retrospective Study.

BACKGROUND: COVID-19 presents with a wide spectrum of clinical and radiological manifestations, including pleural effusion. The prevalence and prognostic impact of pleural effusion are still not entirely clear. PATIENTS AND METHODS: This is a retrospective, single-center study including a population of consecutive patients admitted to the University Hospital of Cisanello (Pisa) from March 2020 to January 2021 with a positive SARS-CoV-2 nasopharyngeal swab and SARS-CoV-2-related pneumonia. The patients were divided into two populations based on the presence (n = 150) or absence (n = 515) of pleural effusion on chest CT scan, excluding patients with pre-existing pleural effusion. We collected laboratory data (hemoglobin, leukocytes, platelets, C-reactive protein, procalcitonin), worst PaO2/FiO2 ratio as an index of respiratory gas exchange impairment, the extent of interstitial involvement related to SARS-CoV-2 pneumonia and data on intensity of care, length of stay and outcome (discharge or death). RESULTS: The prevalence of pleural effusion was 23%. Patients with pleural effusion showed worse gas exchange (p < 0.001), longer average hospital stay (p < 0.001), need for more health care resources (p < 0.001) and higher mortality (p < 0.001) compared to patients without pleural effusion. By multivariate analysis, pleural effusion was found to be an independent negative prognostic factor compared with other variables such as increased C-reactive protein, greater extent of pneumonia and older age. Pleural effusion was present at the first CT scan in most patients (68%). CONCLUSIONS: Pleural effusion associated with SARS-CoV-2 pneumonia is a relatively frequent finding that is confirmed to be a negative prognostic factor. Identifying early prognostic factors in an endemic-prone disease such as COVID-19 is necessary to optimize its clinical management. Further clinical studies aimed at better characterizing pleural effusion in these patients will be appropriate in order to clarify its pathogenetic role.

Evaluation, Description and Magnitude of Readmission Phenomenon in Azienda Ospedaliero Universitaria Pisana (AOUP) for Chronic-Degenerative Diseases in the Period 2018-2021.

BACKGROUND: Readmissions are hospitalizations following a previous hospitalization (called index hospitalization) of the same patient that occurred in the same facility or nursing home. They may be a consequence of the progression of the natural history of a disease, but they may also reveal a previous suboptimal stay, or ineffective management of the underlying clinical condition. Preventing avoidable readmissions has the potential to improve both a patient's quality of life, by avoiding exposure to the risks of re-hospitalization, and the financial well-being of health care systems. METHODS: We investigated the magnitude of 30 day repeat hospitalizations for the same Major Diagnostic Category (MDC) in the Azienda Ospedaliero Universitaria Pisana (AOUP) over the period from 2018 to 2021. Records were divided into only admissions, index admissions and repeated admission. The length of the stay of all groups was compared using analysis of variance and subsequent multi-comparison tests. RESULTS: Results showed a reduction in readmissions over the period examined (from 5.36% in 2018 to 4.46% in 2021), likely due to reduced access to care during the COVID-19 pandemic. We also observed that readmissions predominantly affect the male sex, older age groups, and patients with medical Diagnosis Related Groups (DRGs). The length of stay of readmissions was longer than that of index hospitalization (difference of 1.57 days, 95% CI 1.36-1.78 days, p < 0.001). The length of stay of index hospitalization is longer than that of single hospitalization (difference of 0.62 days, 95% CI 0.52-0.72 days, p < 0.001). CONCLUSIONS: A patient who goes for readmission thus has an overall hospitalization duration of almost two and a half times the length of the stay of a patient with single hospitalization, considering both index hospitalization and readmission. This represents a heavy use of hospital resources, about 10,200 more inpatient days than single hospitalizations, corresponding to a 30-bed ward working with an occupancy rate of 95%. Knowledge of readmissions is an important piece of information in health planning and a useful tool for monitoring the quality of models of patient care.

Evaluation of underreporting tuberculosis in Central Italy by means of record linkage.

BACKGROUND: Tuberculosis (TB) surveillance systems have some pitfalls outside of a National Tuberculosis Program and lack of efficient surveillance hampers accurate epidemiological quantification of TB burden.In the present study we assessed the quality of surveillance at the University Hospital in Pisa (UHP), Italy, and TB incidence rates over a ten year period (1999-2008). METHODS: Assessment of underreporting was done by record-linkage from two sources: databases of TB diagnoses performed in the UHP and the Italian Infectious Disease Surveillance (IIDS) system. Two different databases were examined: a) TB diagnoses reported in the Hospital Discharge Records (HDR) from three Units of UHP (Respiratory Pathophysiology, Pulmonology and Infectious Diseases Units) (TB database A); b) TB diagnoses reported in HDR of all Units of UHP plus TB positive cases obtained by the Laboratory Register (LR) of UHP (TB database B). For the TB database A, the accuracy of TB diagnosis in HDR was assessed by direct examination of the Clinical Record Forms of the cases. For the TB database B, clinical and population data were described, as well as the trend of incidence and underreporting over 10 yrs. RESULTS: In the first study 293 patients were found: 80 patients (27%) with a confirmed TB diagnosis were underreported, 39 of them were microbiologically confirmed. Underreporting was related to age (Reported vs Non Reported, mean age: 49.27 ± 20 vs 55 ± 19, p < 0.005 ), diagnosis (smear positive vs negative cases 18.7 vs 81.2%, p = 0.001), microbiological confirmation (49% vs 51%, p < 0.05), X-ray findings (cavitary vs non-cavitary cases: 12.5 vs 87.5%, p = 0.001) but not to nationality.In the second study, 666 patients were found. Mean underreporting rate was 69.4% and decreased over time (68% in 1999, 48% in 2008). Newly diagnosed TB cases were also found to decrease in number whereas immigration rate increased. Underreporting was related to nationality (Immigrants vs Italians: 18% vs 68%, p < 0.001), diagnosis (microbiological confirmation: 25% vs 75%, p < 0.01), kind of hospital regimen (hospitalized patients vs Day Hospital: 70% vs 16%, p < 0.001), and position of TB code in the HDR (TB code in first position vs in the following position: 39,5% vs 45% p < 0.001). CONCLUSIONS: TB is underreported in Pisa, particularly in older patients and those without microbiological confirmation. The TB code in first position of HDR seems fairly accurate in confirming TB diagnosis.

Accuracy of ADC ratio in discriminating true and false positives in multiparametric prostatic MRI.

PURPOSE: Our goal was to evaluate the usefulness of apparent diffusion coefficient (ADC) ratios in discriminating true from false positives in multiparametric (mp) prostate MRI in clinical practice. METHODS: We retrospectively evaluated 98 prostate lesions in a series of 73 patients who had undergone prostate mpMRI and standard 12-core prostatic biopsy in our institution from 2016 to 2018. Two experienced radiologists performed double blind ADC value quantifications of both MRI-identified lesions and apparently benign contralateral prostatic parenchyma in a circular region of interest (ROI) of ∼10 mm2. The ratios between the mean values of both measurements (i.e., ADC ratio mean) and between the minimum value of the lesion and the maximum value of the benign parenchyma (i.e., ADC ratio min-max) were automatically calculated. The malignancy of all lesions was determined through biopsy according to Gleason score (GS ≥ 6) and localization. RESULTS: For Reader 1, the area under the ROC curve (AUC) of ADC ratio mean and ADC ratio min-max were 0.72 and 0.67, respectively, whereas for Reader 2 these values were 0.74 and 0.71, respectively. The best cut-off values for ADC ratio means were ≥ 0.5 (Reader 1) and ≥ 0.6 (Reader 2), with a sensitivity of 76.3 % and 84.2 % and a specificity of 51.7 % and 50 %, respectively. Moreover, based on a threshold of 0.6, no clinically significant prostate cancer (csPCa) was missed by Reader 1, while only one went unnoticed by Reader 2. CONCLUSION: The ADC ratio is a useful and moderately accurate complementary tool to diagnose prostate cancer in the mp-MRI.

Chest CT accuracy in diagnosing COVID-19 during the peak of the Italian epidemic: A retrospective correlation with RT-PCR testing and analysis of discordant cases.

OBJECTIVES: The goal of this study was to assess chest computed tomography (CT) diagnostic accuracy in clinical practice using RT-PCR as standard of reference. METHODS: From March 4th to April 9th 2020, during the peak of the Italian COVID-19 epidemic, we enrolled a series of 773 patients that performed both non-contrast chest CT and RT-PCR with a time interval no longer than a week due to suspected SARS-CoV-2 infection. The diagnostic performance of CT was evaluated according to sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and diagnostic accuracy, considering RT-PCR as the reference standard. An analysis on the patients with discrepant CT scan and RT-PCR result and on the patient with both negative tests was performed. RESULTS: RT-PCR testing showed an overall positive rate of 59.8 %. CT sensitivity, specificity, PPV, NPV, and accuracy for SARS-CoV-2 infection were 90.7 % [95 % IC, 87.7%-93.2%], 78.8 % [95 % IC, 73.8-83.2%], 86.4 % [95 % IC, 76.1 %-88.9 %], 85.1 % [95 % IC, 81.0 %-88.4] and 85.9 % [95 % IC 83.2-88.3%], respectively. Twenty-five/66 (37.6 %) patients with positive CT and negative RT-PCR results and 12/245 (4.9 %) patients with both negative tests were nevertheless judged as positive cases by the clinicians based on clinical and epidemiological criteria and consequently treated. CONCLUSIONS: In our experience, in a context of high pre-test probability, CT scan shows good sensitivity and a consistently higher specificity for the diagnosis of COVID-19 pneumonia than what reported by previous studies, especially when clinical and epidemiological features are taken into account.

30-Day Potentially Preventable Hospital Readmissions In Older Patients: Clinical Phenotype And Health Care Related Risk Factors.

PURPOSE: Early readmission rate has been regarded as an indicator of in-hospital and post-discharge quality of care. Evaluating the contributing factors is crucial to optimize the healthcare and target the intervention. In this study we evaluated the potential for preventing 30-day hospital readmission in a cohort of older patients and identified possible risk factors for readmission. PATIENTS AND METHODS: Diagnosis-Related Group (DRG) codes of patients consecutively hospitalized for acute disease in the Geriatrics Unit of the University Hospital of Pisa within a 1-year window were recorded. All the patients had received a comprehensive geriatric assessment. Crossing and elaboration of the DRG codes was performed by the Potentially Preventable Readmission Grouping software (3M™ Corporation). DRG codes were classified as stand-alone admissions (SA), index admissions (IA) and potentially preventable readmissions (PPR) within a time window of 30 days after discharge. RESULTS: In total, 1263 SA and 171 IA were identified, with an overall PPR rate of 11.9%. Hospitalizations were significantly longer in IA and PPR than SA (p<0.05). The more frequent readmission causes were acute heart failure, pulmonary edema, sepsis, pneumonia and stroke. In acute heart failure a nonlinear U-shaped readmission trend (with nadir at 5 days of hospitalization) was observed while, in all the other DRG codes, the PPR rate increased with increasing length of hospitalization. Comprehensive geriatric assessment showed a significantly lower degree of disability and comorbidity in SA than IA patients. At stepwise regression analysis, a high degree of disability and comorbidity as well as the diagnosis of sepsis emerged as independent risk factors for PPR. CONCLUSION: Addressing PPR is crucial, especially in older patients. The adequacy of treatment during hospitalization (especially in cases of sepsis) as well as the setting of a comprehensive discharge plan, accounting for comorbidity and disability of the patients, are essential to reduce PPR.

Decreased cardiovascular mortality in the ITALUNG lung cancer screening trial: Analysis of underlying factors.

OBJECTIVES: In the ITALUNG lung cancer screening trial after 9.3 years of follow-up we observed an unexpected significant decrease of cardiovascular (CV) mortality in subjects invited for low-dose CT (LDCT) screening as compared to controls undergoing usual care. Herein we extended the mortality follow-up and analyzed the potential factors underlying such a decrease. MATERIALS AND METHODS: The following factors were assessed in screenes and controls: burden of CV disease at baseline, changes in smoking habits, use of CV drugs and frequency of planned vascular procedures after randomisation. Moreover, in the screenes we evaluated inclusion of presence of coronary artery calcification (CAC) in the LDCT report form that was transmitted to the participant and his/her General Practitioner. RESULTS: The 2-years extension of follow-up confirmed a significant decrease of CV mortality in the subjects of the active group compared to control subjects (15.6 vs 34.0 per 10,000; p = 0.001) that was not observed in the drops-out of the active group. None of the explaining factors we considered significantly differed between active and control group. However, the subjects of the active group with reported CAC experienced a not significantly lower CV mortality and showed a significantly higher use of CV drugs and frequency of planned vascular procedures than the control group. CONCLUSIONS: LDCT screening for lung cancer offers the opportunity for detection of CAC that is an important CV risk factor. Although the underlying mechanisms are not clear, our results suggest that the inclusion of information about CAC presence in the LDCT report may represent a candidate factor to explain the decreased CV mortality observed in screened subjects of the ITALUNG trial, possibly resulting in intervention for patient care to prevent CV deaths. Further studies investigating whether prospective reporting and rating of CAC have independent impact on such interventions and CV mortality are worthy.

Role of perfusion defects at follow-up lung scan in predicting recurrences after a first episode of symptomatic pulmonary embolism: a retrospective analysis.

: The optimal duration of anticoagulant therapy after a first episode of unprovoked pulmonary thromboembolism is not fully defined. The identification of patients more prone to recurrence would be useful in this context but is currently relatively unreliable. Perfusion lung scan (PLS) is an established approach for the follow-up of patients with pulmonary embolism to identify recurrences and to help in the diagnosis of chronic thromboembolic pulmonary hypertension. The aim of the study was to investigate the potential role of residual perfusion defects at follow-up perfusion scans in predicting pulmonary embolism recurrences. We retrospectively analyzed PLSs of 252 patients with a first episode of unprovoked, symptomatic pulmonary embolism. The agreement between two experienced readers, as assessed by the kappa test, was good, with kappa indices ranging from 0.84 (baseline scan) to 0.98 (last prerecurrence available scan). Sixteen patients developed a late (at least 1 month from the index episode) recurrence identified through the appearance of (a) new perfusion defect(s) not matching radiograph alterations. When patients were divided based on the presence or absence of at least two unperfused segments at the 6-month follow-up lung scan, the probability of recurrence was significantly higher in the latter (P = 0.03 by log-rank test). The use of persistent perfusion defects at follow-up PLS as a guide to determine optimal duration of anticoagulant therapy after a first, unprovoked episode of acute pulmonary thromboembolism is a viable strategy that should be further investigated.

Five-year follow-up of pulmonary embolism under anticoaugulation: The PISA-PEET (Pulmonary Embolism Extension Therapy) study.

Benefits and harms of long-term anticoagulant therapy (AT) after acute pulmonary embolism (PE) are poorly known. The aim of this study was to investigate the outcome of patients with PE treated with AT for 5 years according to American College of Chest Physicians (ACCP) guidelines.Patients with both unprovoked and secondary PE were consecutively enrolled in a "real life" study. After a 12-month AT, they continued or stopped the treatment according to ACCP guidelines, and were followed-up for 5 years. Outcomes were all-cause mortality, recurrence, and fatal recurrence under AT.Of the original consecutive 585 patients, 471 were included (83 dead, 31 lost during the 1st year). Of these, 361 (76.6%) continued AT. During 5 years, death occurred in 109 (30.2%) patients, with a mortality rate of 8.00 events/100 person-years of follow-up; recurrence in 34 (9.4%), with an incidence rate of 2.58 events/person-years; fatal recurrence in 13 (3.6%), with an incidence rate of 0.95 events/person-years. The case fatality rate for recurrence was 38.2%. In the subgroup of patients with unprovoked PE, the chance of dying was significantly lower (RR 0.35; 95% confidence interval 0.24-0.53) and the tendency to fatal recurrence (not significantly) greater (0.11 events/100 person-years vs 0.07 events/100 person-years) than in the remaining patients. Major bleeding occurred in 5 (1.3%) patients. The case fatality rate for bleeding was 14.3%.During 5-year AT, 30% of patients dies, 10% experiences recurrences, and 5% has fatal recurrences. According to guidelines, most patients need to continue AT; the case fatality rate for bleeding is lower than that for recurrence.

Application of a pharmacokinetic/pharmacogenetic approach to assess the nicotine metabolic profile of smokers in the real-life setting.

The nicotine metabolite ratio, i.e., the ratio 3-hydroxycotinine/cotinine, is used to assess the nicotine metabolic status and has been proven to predict the response to smoking cessation treatments in randomized clinical trials. In the current study, a pharmacokinetic-pharmacogenetic integrated approach is described, based on the development of a liquid chromatography-tandem mass spectrometry (LC/MS/MS) method for nicotine metabolite ratio assay in plasma and a real-time PCR analysis for fast genotyping of CYP2A6. The pharmacokinetic-pharmacogenetic approach was validated in 66 subjects with different smoking status. The LC/MS/MS assay was rapid and sensitive enough to detect plasma cotinine levels also in second-hand exposed abstainers. In the cohort of patients of the present study the following results were obtained: (i) the frequencies of CYP2A6 genetic variants were comparable with those from clinical trials carried out in Caucasian populations; (ii) all the subjects carrying the CYP2A6 deficient allele also had a slow metabolizer phenotype; (iii) slow metabolizers had mean nicotine metabolite ratio approximately 50% of that of the normal/fast metabolizers; (iv) women had higher nicotine metabolite ratio than men; and (v) salivary nicotine metabolite ratio measures were comparable to plasma levels. Overall, the findings of the current study demonstrate that the simultaneous assessment of nicotine metabolite ratio and CYP2A6 genotype from human blood samples is feasible and accurate and could be used in a smoking cessation program to optimize treatments and identify those smokers who inherit metabolically deficient CYP2A6 alleles.