Cigarette smoking and lung cancer--relative risk estimates for the major histological types from a pooled analysis of case-control studies

Lung cancer is mainly caused by smoking, but the quantitative relations between smoking and histologic subtypes of lung cancer remain inconclusive. By using one of the largest lung cancer datasets ever assembled, we explored the impact of smoking on risks of the major cell types of lung cancer. This pooled analysis included 13,169 cases and 16,010 controls from Europe and Canada. Studies with population controls comprised 66.5% of the subjects. Adenocarcinoma (AdCa) was the most prevalent subtype in never smokers and in women. Squamous cell carcinoma (SqCC) predominated in male smokers. Age-adjusted odds ratios (ORs) were estimated with logistic regression. ORs were elevated for all metrics of exposure to cigarette smoke and were higher for SqCC and small cell lung cancer (SCLC) than for AdCa. Current male smokers with an average daily dose of >30 cigarettes had ORs of 103.5 (95% confidence interval (CI): 74.8-143.2) for SqCC, 111.3 (95% CI: 69.8-177.5) for SCLC and 21.9 (95% CI: 16.6-29.0) for AdCa. In women, the corresponding ORs were 62.7 (95% CI: 31.5-124.6), 108.6 (95% CI: 50.7-232.8) and 16.8 (95% CI: 9.2-30.6), respectively. Although ORs started to decline soon after quitting, they did not fully return to the baseline risk of never smokers even 35 years after cessation. The major result that smoking exerted a steeper risk gradient on SqCC and SCLC than on AdCa is in line with previous population data and biological understanding of lung cancer development.     

Bone effect of adjuvant tamoxifen, letrozole or letrozole plus zoledronic acid in early-stage breast cancer: the randomized phase 3 HOBOE study

BackgroundTo measure bone mineral density (BMD) reduction produced by letrozole as compared with tamoxifen and the benefit of the addition of zoledronic acid.Patients and methodsA phase 3 trial comparing tamoxifen, letrozole or letrozole + zoledronic acid in patients with hormone receptor-positive early breast cancer was conducted; triptorelin was given to premenopausal patients. Two comparisons were planned: letrozole versus tamoxifen and letrozole + zoledronic acid versus letrozole. Primary end point was the difference in 1-year change of T-score at lumbar spine (LTS) measured by dual energy X-ray absorptiometry scan.ResultsOut of 483 patients enrolled, 459 were available for primary analyses. Median age was 50 (range 28–80). The estimated mean difference (95% confidence interval [CI]) in 1-year change of LTS was equal to -0.30 (95% CI -0.44 to -0.17) in the letrozole versus tamoxifen comparison (P < 0.0001) and to +0.60 (95% CI +0.46 to +0.77) in the letrozole + zoledronic acid versus letrozole comparison (P < 0.0001). Bone damage by letrozole decreased with increasing baseline body mass index in premenopausal, but not postmenopausal, patients (interaction test P = 0.004 and 0.47, respectively).ConclusionsIn the HOBOE (HOrmonal BOne Effects) trial, the positive effect of zoledronic acid on BMD largely counteracts damage produced by letrozole as compared with tamoxifen. Letrozole effect is lower among overweight/obese premenopausal patients.     

Genetic determinants for promoter hypermethylation in the lungs of smokers: a candidate gene-based study

The detection of tumor suppressor gene promoter methylation in sputum-derived exfoliated cells predicts early lung cancer. Here, we identified genetic determinants for this epigenetic process and examined their biologic effects on gene regulation. A two-stage approach involving discovery and replication was used to assess the association between promoter hypermethylation of a 12-gene panel and common variation in 40 genes involved in carcinogen metabolism, regulation of methylation, and DNA damage response in members of the Lovelace Smokers Cohort (N = 1,434). Molecular validation of three identified variants was conducted using primary bronchial epithelial cells. Association of study-wide significance (P < 8.2 × 10(-5)) was identified for rs1641511, rs3730859, and rs1883264 in TP53, LIG1, and BIK, respectively. These single-nucleotide polymorphisms (SNP) were significantly associated with altered expression of the corresponding genes in primary bronchial epithelial cells. In addition, rs3730859 in LIG1 was also moderately associated with increased risk for lung cancer among Caucasian smokers. Together, our findings suggest that genetic variation in DNA replication and apoptosis pathways impacts the propensity for gene promoter hypermethylation in the aerodigestive tract of smokers. The incorporation of genetic biomarkers for gene promoter hypermethylation with clinical and somatic markers may improve risk assessment models for lung cancer.     

Aortic size in acute type A dissection: implications for preventive ascending aortic replacement

Objective: Elective ascending aortic replacement is recommended to prevent acute type A aortic dissection when any segment of the proximal aorta is greater than 5.5 cm. However, little data exist that meticulously describe the size of the ascending aorta at multiple levels in patients who suffer acute type A dissections. We sought to definitively characterize the size distribution of the proximal aorta in this patient population. Methods: Preoperative transesophageal echocardiography was used to measure the diameter of the proximal aorta at the aortic annulus, in the sinus segment, at the sinotubular junction and in the ascending aorta in 177 non-Marfan patients with tricuspid aortic valves who presented to one institution over a 10-year period with an acute type A dissection. Predicted aortic diameters for each patient based on the individual's age, gender and body size were also calculated at all four aortic positions using previously published regression equations derived from a large cohort of normal patients. Results: Sixty patients were female (33.9%; aged 67 ± 12 years) and 117 were male (66.1%; aged 60 ± 17 years). Sixty-two percent of all patients had maximum aortic diameters less than 5.5 cm at time of dissection and 42% of patients had maximum aortic diameters less than 5.0 cm. Over 20% of all patients had maximal aortic dimensions of less than 4.5 cm. In women, 12% of the dissected aortas had a maximal dimension less than 4.0 cm. Conclusions: The majority of patients with acute type A aortic dissection present with aortic diameters <5.5 cm and thus do not fall within current guidelines for elective ascending aortic replacement. Methods other than size measurement of the ascending aorta are needed to identify patients at risk for dissection. Aggressive medical management of patients with ascending aortic diameters over 4 cm is warranted. Preventative replacement of the ascending aorta at 4.5 cm should be considered especially at high volume aortic surgery centers and patients having cardiac surgery for other indications.     

Immunomagnetic selection of progenitor cells from peripheral blood after thawing with an automatic system in a pediatric patient with a neuroblastoma

BACKGROUND: Immunomagnetic selection of peripheral blood progenitor cells (PBPCs) in patients with tumoral infiltration in marrow makes it possible to reduce contamination of cellular concentrates, but this procedure cannot always be used, mainly because of the low cellular count in apheresis concentrates. STUDY DESIGN AND METHODS: In this case two cellular concentrates taken separately at two different times were selected and cryopreserved; they were thawed with an automatic instrument. RESULTS: After manipulation, a selected concentrate containing 24.16 x 106 CD34+ cells with a purity of 90.15 percent was obtained; vitality after thawing and selection was 88 and 96 percent, respectively. The engraftment was achieved on Day +17 from the infusion of the previously selected PBPCs, as the literature also shows us. CONCLUSION: The time passed between the infusion and the engraftment gives us evidence of the efficacy of immunomagnetic selection carried out after thawing 2 cell units that were collected at different times from the same patient. In this way, it has been possible to perform an autologous transplant in a patient in which CD34+ cells transplant is recommended, but from whom the number of collected cells after a single mobilization cycle would not have been sufficient for the engraftment.     

Cetuximab efficacy in patients treated routinely in university hospitals

INTRODUCTION: The aim of this study was to evaluate the efficacy and tolerance of cetuximab (Cx) in patients with irinotecan-refractory metastatic colorectal cancer (IRMCRC) treated routinely at five university hospitals. PATIENTS AND METHODS: Data from all patients treated with Cx (N=105) during the study period (between January 2004 and September 2005) were included in the analysis. RESULTS: Median number of Cx infusions was 12 (range: 1 to 62). Objective response rate was 24.8%; stable disease in 23.8%; progression in 34.3%; 17.1% of the patients were not evaluable. Digestive and hematological adverse events were grade III in 20% and 12%, respectively, and grade IV in 12% and 11%, respectively. Response rates were higher in patients with acne-like rashes than in patients without (P=0.005). Median time to tumor progression (TTP; intention-to-treat) was 3.9 months (95% CI: 2.6-4.8). Median overall survival after Cx initiation was 8.3 months (95% CI: 6.310.7). Four prognostic factors were significantly associated with a shorter TTP: center (Center 4: HR=2.25, 95% CI: 1.16-4.35, P=0.017); absence of hepatic metastases (HR=2.5, 95% CI: 1.434.37, P=0.001); WHO performance status (HR=1.47, 95% CI: 1.10-1.96, P=0.008); and number of metastatic sites (HR=1.30, 95% CI: 1.05-1.60, P=0.014). CONCLUSION: This analysis of a random population of IRMCRC patients supports Cx efficacy and feasibility, and is in agreement with the results of the BOND study.     

Endoscopic management of a large choledochocele associated with choledocholithiasis

Choledochocele or type III choledochal cyst is a very rare lesion, defined as a cystic dilatation of the distal common bile duct protruding into the duodenal lumen. Abdominal pain, biliary disorders, and acute pancreatitis are frequently observed but malignant degeneration is rare. A 70-year-old man had a history of epigastralgia associated with abnormal liver function tests suggesting gallstones. During laparoscopic cholecystectomy, intraoperative cholangiography showed a 40-mm-diameter choledochocele associated with choledocholithiasis. A transcystic drain was placed after cholecystectomy had been completed. Endoscopic retrograde cholangiopancreatography confirmed the diagnosis and a 45-mm-long endoscopic sphincterotomy successfully treated both lesions as confirmed by a transcystic cholangiogram showing a thin-walled common bile duct with no residual stones. This case illustrates that the diagnosis of choledochocele remains difficult in clinical practice and confirms that endoscopic retrograde cholangiopancreatography is the best available diagnostic tool. Coexistent choledocholithiasis is observed in about 20% of choledochocele. Endoscopic sphincterotomy is feasible and effectively treats both lesions even in larger choledochoceles.     

Association of calcium channel blocker use and pregnancy-associated plasma protein-A among older adults with hypertension: results from the ilSIRENTE study

BACKGROUND: Pregnancy-associated plasma protein A (PAPP-A) is a zinc-binding matrix metalloproteinase (MMP) that was shown to increase in acute coronary syndromes. Calcium channel blockers (CCB) can influence the production of several MMPs, but no study, so far, has assessed the association between use of CCB and PAPP-A levels. The aim of the present cross-sectional study was to evaluated if, among older hypertensive adults, PAPP-A levels differ according to use of CCB. METHODS: Data are from the baseline evaluation of the ilSIRENTE study, which enrolled 364 participants 80 years old or older. For the present study, we selected 314 participants with hypertension. Analyses of covariance were performed to evaluate the differences in PAPP-A levels according to use of CCB. RESULTS: Mean age of participants was 85.6 years (standard deviation [SD] 4.8), 206 (66%) were women; 58 participants (19%) were using a CCB. After adjusting for potential confounders, concentration of PAPP-A was significantly lower in CCB users than in nonusers (1.58 mIU/L, 95% confidence interval [CI], 1.37-1.81 vs 1.86 mIU/L, 95% CI, 1.74-1.98; p =.03). This association was still consistent after exclusion of participants with cardiovascular disease (1.53 mIU/L, 95% CI, 1.30-1.80 vs 1.90 mIU/L, 95% CI, 1.78-2.03; p =.01). CONCLUSIONS: Use of CCB is associated with lower levels of PAPP-A. These findings need to be confirmed in prospective studies.     

Depression and physical function: results from the aging and longevity study in the Sirente geographic area (ilSIRENTE Study)

Depression in older persons represents a major issue because of its relevant prevalence and the associated higher risk of adverse health-related events. The aim of this study was to evaluate the relationship of depressive symptoms with measures of physical performance, muscle strength, and functional status. Data are from baseline evaluation of the ilSIRENTE Study (n = 364). Physical performance was assessed using the Short Physical Performance Battery and the 4-meter walking test. Muscle strength was measured by hand-grip strength. Functional performance was assessed using Basic and Instrumental Activities of Daily Living. Depression was defined by analyzing the different depressive manifestations included in the Minimum Data Set for Home Care Form: verbal expression of sad and/or anxious mood and demonstrated signs of mental distress. Analyses of covariance and linear regressions were performed to evaluate the relationship between depression and physical function. Participants with depression showed significantly worse results in all of the physical function tests. Subjects with depression presented significantly lower adjusted mean results for the 4-meter walking test (0.41 m/s; SE, 0.03) and the Short Physical Performance Battery score (5.68; SE, 0.38) compared with those without depression (0.50 m/s; SE, 0.01 and 6.93; SE, 0.21; all P < .01, respectively). Participants with depressed mood also presented a higher number of impaired instrumental activities of daily living (3.69; SE, 0.25) compared with participants with less than 3 depressive symptoms (2.85; SE, 0.14; P = .005). No significant difference was reported for the hand-grip strength and the Basic Activities of Daily Living scale. In conclusion, physical performance and functional status measures are significantly and negatively influenced by the presence of depression in community-dwelling older persons aged 80 years and older.