Silvia Quadrelli

Multiplexed methylation profiles of tumor suppressor genes and clinical outcome in lung cancer.

BackgroundChanges in DNA methylation of crucial cancer genes including tumor suppressors can occur early in carcinogenesis, being potentially important early indicators of cancer. The objective of this study was to examine a multiplexed approach to assess the methylation of tumor suppressor genes as tumor stratification and clinical outcome prognostic biomarkers for lung cancer.MethodsA multicandidate probe panel interrogated DNA for aberrant methylation status in 18 tumor suppressor genes in lung cancer using a methylation-specific multiplex ligation-dependent probe amplification assay (MS-MLPA). Lung cancer cell lines (n = 7), and primary lung tumors (n = 54) were examined using MS-MLPA.ResultsGenes frequently methylated in lung cancer cell lines including SCGB3A1, ID4, CCND2 were found among the most commonly methylated in the lung tumors analyzed. HLTF, BNIP3, H2AFX, CACNA1G, TGIF, ID4 and CACNA1A were identified as novel tumor suppressor candidates methylated in lung tumors. The most frequently methylated genes in lung tumors were SCGB3A1 and DLC1 (both 50.0%). Methylation rates for ID4, DCL1, BNIP3, H2AFX, CACNA1G and TIMP3 were significantly different between squamous and adenocarcinomas. Methylation of RUNX3, SCGB3A1, SFRP4, and DLC1 was significantly associated with the extent of the disease when comparing localized versus metastatic tumors. Moreover, methylation of HTLF, SFRP5 and TIMP3 were significantly associated with overall survival.ConclusionsMS-MLPA can be used for classification of certain types of lung tumors and clinical outcome prediction. This latter is clinically relevant by offering an adjunct strategy for the clinical management of lung cancer patients.

Follow-up and Surveillance of the Patient With Lung Cancer After Curative-Intent Therapy: Diagnosis and Management of Lung Cancer, 3rd ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

BACKGROUND These guidelines are an update of the evidence-based recommendations for follow-up and surveillance of patients after curative-intent therapy for lung cancer. Particular updates pertain to whether imaging studies, health-related quality-of-life (HRQOL) measures, tumor markers, and bronchoscopy improve outcomes after curative-intent therapy. METHODS Meta-analysis of Observational Studies in Epidemiology guidelines were followed for this systematic review, including published studies on posttreatment outcomes in patients who received curative-intent therapy since the previous American College of Chest Physicians subject review. Four population, intervention, comparison, and outcome questions were formulated to guide the review. The MEDLINE and CINAHL databases were searched from June 1, 2005, to July 8, 2011, to ensure overlap with the search strategies used previously. RESULTS A total of 3,412 citations from MEDLINE and 431 from CINAHL were identified. Only 303 were relevant. Seventy-six of the 303 articles were deemed eligible on the basis of predefined inclusion criteria after full-text review, but only 34 provided data pertaining directly to the subject of the questions formulated to guide this review. In patients undergoing curative-intent surgical resection of non-small cell lung cancer, chest CT imaging performed at designated time intervals after resection is suggested for detecting recurrence. It is recommended that treating physicians who are able to incorporate the patients clinical findings into decision-making processes be included in follow-up and surveillance strategies. The use of validated HRQOL instruments at baseline and during follow-up is recommended. Biomarker testing during surveillance outside clinical trials is not suggested. Surveillance bronchoscopy is suggested for patients with early central airway squamous cell carcinoma treated by curative-intent photodynamic therapy and for patients with intraluminal bronchial carcinoid tumor who have undergone curative-intent bronchoscopic treatment with Nd:YAG laser or electrocautery. CONCLUSIONS There is a paucity of well-designed prospective studies specifically targeting follow-up and surveillance modalities aimed at improving survival or QOL after curative-intent therapy. Additional research is warranted to clarify which curative-intent treatment modalities affect HRQOL the most and to identify patients who are at the most risk for recurrence or impaired QOL after treatment. Further evidence is needed to determine how the frequency and duration of surveillance programs that include imaging studies, QOL measurements, tumor markers, or bronchoscopy affect patient morbidity, survival, HRQOL, and health-care costs.

Is asthma in the elderly really different

To examine the nature of asthma in the elderly, we compared older (group 1: 65 years or older, n = 50) with younger patients (group 2: <40 years, n = 99) and to determine the influence of long-standing disease, elderly asthmatics with early onset (group A: onset before 40, n = 22) were compared with patients developing symptoms later in their lives (group B: onset after 40, n = 22). Blood eosinophilia and IgE value ≥100 IU/l were more frequent in younger patients. Short symptom-free periods were more frequent among older asthmatics (78.5 vs. 45.4%, p < 0.001). Only 31.2% of older patients had only mild symptoms. Requirement of systemic steroids was higher in the elderly population. The worst FEV1 was lower in older patients (54.4 ± 17.3 vs. 71.8 ± 18.5%, p {FC96}& 0.001). Patients with early-onset asthma showed more frequently shorter symptom-free periods (93.3 vs. 53.3%, p <0.05), higher emergency admissions/year, and hospitalizations/year. Best FEV1 (group 1: 66.7 ± 13.7% vs. group 2: 90.3 ± 15.1%, p < 0.005) and worst FEV1 (46.2 ± 13.1 vs. 61.0 ± 13.2%, p < 0.01) were lower in early-onset patients. A higher systemic steroid requirement, a lower best and worst FEV1, shorter symptom-free periods and a lesser proportion of patients with only mild symptoms were observed in patients older than 65 with early-onset asthma compared with those younger than 40 years. Elderly patients with a shorter duration of asthma were not different from young patients. Our study strongly suggests that severity of asthma and development of irreversible airflow obstruction depend on the duration of disease.

Features of Asthma in the Elderly

Asthma has been considered a rare disease in the elderly, but recent studies have shown that it is as common in the elderly as in the middle-aged population. Diagnosis of asthma is often overlooked in older patients, leading to undertreatment. Spirometry, determination of expiratory flow lability, and histamine challenge tests are tools that are as useful for the evaluation of elderly asthmatics as they are for younger patients. Asthma is more severe in the elderly, especially in long-standing asthmatics. Treatment of asthma in the elderly should follow the same stepwise guidelines that are recommended for all age groups, though it will require more intense monitoring. An aggressive treatment approach to mild and moderate asthma in young people is the best hope of changing the future trends of asthma in the elderly.

Evaluation of bronchodilator response in patients with airway obstruction

The aim of this study was to define the most useful index of expressing bronchodilator response and to distinguish between asthma and COPD. A prospective study was carried out of bronchodilator response in 142 asthmatics and 58 COPD patients in a university hospital. Reversibility was expressed as: 1. absolute change (delta abs); 2. % of initial (delta %init); 3. % of predicted (delta %pred) and 4. % of maximum possible response (delta %max). Dependence on forced expirations volume in 1 sec (FEV1) as % of predicted and sensitivity and specificity for diagnosis of asthma were established. A relationship between delta abs and initial FEV1 was not found in asthma (delta abs vs. % initial FEV1. r = 0.07) or COPD (r = 0.02). delta %pred did not show a correlation in asthma (r = 0.10) or COPD (r = 0.06). delta %init was dependent on the baseline value in asthma (r = 0.38, P < or = 0.001) but not in COPD (r = 0.18, P = n.s.). delta max was dependent in both. The combination of best sensitivity and specificity to separate asthma and COPD was obtained with delta abs (70.4 or 70.6%). The worst specificity for asthma diagnosis was obtained with delta %init (50%). The best likelihood ratios were obtained with delta abs and delta %pred and the worst likelihood ratio with delta %init. delta %init is not recommended as an index for differential diagnosis between asthma and COPD; 2) delta %init overscores bronchodilator response in patients with low FEV1. The independence of each bronchodilator response index should be verified in clinical trials for each selected sample.

Reliability of a 25-Item Low-Stakes Multiple-Choice Assessment of Bronchoscopic Knowledge

BACKGROUND A need for improved patient safety, quality of care, and accountability has prompted the development of competency-based educational processes. Assessment tools related to bronchoscopy training, however, have not yet been developed or validated. PURPOSES To determine whether 25 multiple-choice questions (MCQs) extracted from the free, Web-based Essential Bronchoscopist (EB) learning guide qualify in their original form as a preliminary pool of questions for a low-stakes assessment of bronchoscopic knowledge. MATERIALS AND METHODS Twenty-five randomly selected MCQs from among the top 70 question-answer sets of the EB were administered to 40 self-declared novice bronchoscopists (n = 13), experienced bronchoscopists (n = 21), and expert bronchoscopists (n = 6). A difficulty index and a discrimination index (DI) were calculated for each item. Internal consistency reliability was calculated using item-total correlation and Cronbach alpha. Content validity was determined by five independent experts. Ideal test items based on a difficulty index and item-total correlation were administered to a different group of 24 bronchoscopists to prospectively reassess internal consistency reliability. RESULTS The mean (+/- SD) score for the 40 participants was 16.47 +/- 3.72 (median score, 17; score range, 7 to 22). The mean difficulty index was 0.65 +/- 0.22, and the mean DI was 0.52 +/- 0.28. Item total-correlations ranged from - 0.01 to + 0.71. Test content was unanimously validated. The Cronbach alpha was 0.69. There was no significant correlation between scores and the number of bronchoscopies performed or self-declared expertise. Eleven ideal test MCQs were identified. The internal consistency of these items remained satisfactory (Cronbach alpha = 0.75) when assessed prospectively in a different cohort. CONCLUSION Reliable and valid MCQs were identified to initiate a preliminary pool of questions for a low-stakes assessment of bronchoscopic knowledge.

Radiological versus histopathological diagnosis of usual interstitial pneumonia in the clinical practice: does it have any survival difference?

Background: Recent studies have shown that quantification of specific histopathologic features found in usual interstitial pneumonia (UIP) are useful in defining a prognosis, suggesting the need of biopsy in all patients. Objectives: This study examines whether UIP-associated mortality is different in patients diagnosed by high-resolution computed tomography (HRCT) features considered definite of UIP and in patients with no definite radiological diagnosis that required histological confirmation of diagnoses. Methods: Forty-five patients were included (30 males, mean age 65.3 ± 10.7 years). Two groups of patients were identified: those with HRCT findings of definite UIP (n = 26) and those whose radiological diagnosis was not definite and required a surgical biopsy to confirm the presence of UIP (n = 19). Forced vital capacity, forced expiratory volume in 1 s and diffusing capacity for carbon monoxide were measured in all patients. All data were obtained from medical records, and the survival status was obtained by telephone or personal interview. All clinical parameters and HRCTs were obtained within 1 month before surgical lung biopsy. Results: Median survival was not different across groups and was similar to that previously reported (35 months). Kaplan-Meier analysis did not show any difference in 5-year survival between both groups. Conclusions: In a clinical context in which the diagnosis of UIP can be obtained as a dynamic process that includes an integrated clinical, radiological and pathologic approach, a reliable diagnosis of UIP can be obtained based on a typical definite HRCT with no risk of including patients with a more benign disease and a more prolonged survival.

A competency-based test of bronchoscopic knowledge using the Essential Bronchoscopist: an initial concept study.

Background and objective:  Competency‐based training and assessment are increasingly replacing the traditional structure‐ and process‐based model of medical education. The web‐based Essential Bronchoscopist (EB) is an open access, laddered, competency‐based curriculum of question‐answer sets pertaining to basic bronchoscopic knowledge, accessible in five languages. The purpose of this study was to use consensus to evaluate whether question‐answer sets (items) from the EB could provide material from which to devise competency‐based tests of bronchoscopic knowledge that could be used in countries with different health‐care environments.

Analysis of Survival in 400 Surgically Resected Non-small Cell Lung Carcinomas: Towards a Redefinition of the T Factor

Introduction: The tumor, node, metastasis (TNM) system has been recognized internationally as the standard for staging disease extension, but despite the improvements of the 1997/2002 international staging system, there may be marked differences in postoperative 5-year survival rates within each stage. There is controversy about the impact of tumor size itself as a variable unrelated to stage. The objective of this study was to analyze the influence of tumor size on the survival in patients with surgically resected non-small cell lung carcinoma (NSCLC). Methods: Between August 1985 and January 2006, 400 patients underwent pulmonary resection with a curative intention for non-small cell lung carcinoma. Patients were excluded if they had received neoadjuvant chemotherapy. The clinicopathological records of each patient were examined for prognostic factors such as age, sex, right or left side cancer, histology, tumor location, tumor size, clinical nodal stage number, and distribution of metastatic nodes. Results: Operative mortality was 2.2% for lobectomy and 18% for pneumonectomy (p < 0.05). Adenocarcinoma was the most common type (n = 245, 61.2%). Surgery was considered a complete resection in 341 patients (85.2%). When only patients without neoplastic hilar or mediastinal metastases (pN0) were included, the difference in survival was significantly different in terms of tumor size (log rank 28.46, p < 0.0001). Univariate analysis for the group of pN0 patients showed survival was not significantly affected by age, sex, side, or adenocarcinoma histology. In the multivariate analysis, tumor size and the T factor were found to have maintained its independent prognostic effects on overall survival. Among patients with pN0 tumors smaller that 15 mm in diameter, 5-year survival was 95% whereas patients with tumors bigger than 16 mm in diameter had a 5-year survival of 65% (p < 0.0001). Conclusion: In conclusion, our data suggest that tumors over 15 mm are associated with shorter 5-year survival in all TNM stages. Current TNM categories are not sufficiently discriminatory and the T factor requires to be reevaluated in further revisions of the TNM classification.

Use of Competency-Based Metrics to Determine Effectiveness of a Postgraduate Thoracoscopy Course

Background: Despite the paradigm shift from process to competency-based education, no study has explored how competency-based metrics might be used to assess short-term effectiveness of thoracoscopy-related postgraduate medical education. Objectives: To assess the use of a single-group, pre-/post-test model comprised of multiple-choice questions (MCQ) and psychomotor skill measures to ascertain the effectiveness of a postgraduate thoracoscopy program. Methods: A 37-item MCQ test of cognitive knowledge was administered to 17 chest physicians before and after a 2-day continued medical education-approved program. Pre- and post-course technical skills were assessed using rigid videothoracoscopy simulation stations. Competency-based metrics (mean relative gain, mean absolute gain, and class-average normalized gain ) were calculated. A >30% was used to determine curricular effectiveness. Results: Mean cognitive knowledge score improved significantly from 20.9 to 28.7 (7.8 ± 1.3 points, p < 0.001), representing a relative gain of 37% and an absolute gain of 21%. Mean technical skill score improved significantly from 5.20 to 7.82 (2.62 ± 0.33 points, p < 0.001), representing a relative gain of 50% and an absolute gain of 33%. Non-parametric testing confirmed t test results (p < 0.001). Class-average normalized gains were 48 and 92%, respectively. Conclusion: Competency-based metrics, including class-average normalized gain, can be used to assess course effectiveness and to determine if a program meets predesignated objectives of knowledge acquisition and psychomotor technical skill.