H. M. Boezen

Increased risk of fundic gland polyps during long-term proton pump inhibitor therapy

It is controversial whether proton pump inhibitor use leads to fundic gland polyp development.

Circulating tumor cells in small-cell lung cancer: a predictive and prognostic factor

BACKGROUNDnInitial response of small-cell lung cancer (SCLC) to chemotherapy is high, and recurrences occur frequently, leading to early death. This study investigated the prognostic value of circulating tumor cells (CTCs) in patients with SCLC and whether changes in CTCs can predict response to chemotherapy. Patients and methods In this multicenter prospective study, blood samples for CTC analysis were obtained from 59 patients with SCLC before, after one cycle, and at the end of chemotherapy. CTCs were measured using CellSearch systems.nnnRESULTSnAt baseline, lower numbers of CTCs were observed for 21 patients with limited SCLC (median = 6, range 0-220) compared with 38 patients with extensive stage (median = 63, range 0-14,040). Lack of measurable CTCs (27% of patients) was associated with prolonged survival (HR 3.4; P ≤ 0.001). CTCs decreased after one cycle of chemotherapy; this decrease was not associated with tumor response after four cycles of chemotherapy. CTC count after the first cycle of chemotherapy was the strongest predictor for overall survival (HR 5.7; 95% CI 1.7-18.9; P = 0.004).nnnCONCLUSIONnAbsolute CTCs after one cycle of chemotherapy in patients with SCLC is the strongest predictor for response on chemotherapy and survival. Patients with low initial CTC numbers lived longer than those with higher CTCs.BACKGROUNDnInitial response of small-cell lung cancer (SCLC) to chemotherapy is high, and recurrences occur frequently, leading to early death. This study investigated the prognostic value of circulating tumor cells (CTCs) in patients with SCLC and whether changes in CTCs can predict response to chemotherapy.nnnPATIENTS AND METHODSnIn this multicenter prospective study, blood samples for CTC analysis were obtained from 59 patients with SCLC before, after one cycle, and at the end of chemotherapy. CTCs were measured using CellSearch® systems.nnnRESULTSnAt baseline, lower numbers of CTCs were observed for 21 patients with limited SCLC (median = 6, range 0-220) compared with 38 patients with extensive stage (median = 63, range 0-14 040). Lack of measurable CTCs (27% of patients) was associated with prolonged survival (HR 3.4; P ≤ 0.001). CTCs decreased after one cycle of chemotherapy; this decrease was not associated with tumor response after four cycles of chemotherapy. CTC count after the first cycle of chemotherapy was the strongest predictor for overall survival (HR 5.7; 95% CI 1.7-18.9; P = 0.004).nnnCONCLUSIONnAbsolute CTCs after one cycle of chemotherapy in patients with SCLC is the strongest predictor for response on chemotherapy and survival. Patients with low initial CTC numbers lived longer than those with higher CTCs.

CT-quantified emphysema in male heavy smokers: association with lung function decline

Background Emphysema and small airway disease both contribute to chronic obstructive pulmonary disease (COPD), a disease characterised by accelerated decline in lung function. The association between the extent of emphysema in male current and former smokers and lung function decline was investigated. Methods Current and former heavy smokers participating in a lung cancer screening trial were recruited to the study and all underwent CT. Spirometry was performed at baseline and at 3-year follow-up. The 15th percentile (Perc15) was used to assess the severity of emphysema. Results 2085 men of mean age 59.8u2005years participated in the study. Mean (SD) baseline Perc15 was −934.9 (19.5)u2005HU. A lower Perc15 value correlated with a lower forced expiratory volume in 1u2005s (FEV1) at baseline (r=0.12, p<0.001). Linear mixed model analysis showed that a lower Perc15 was significantly related to a greater decline in FEV1 after follow-up (p<0.001). Participants without baseline airway obstruction who developed it after follow-up had significantly lower mean (SD) Perc15 values at baseline than those who did not develop obstruction (−934.2 (17.1)u2005HU vs −930.2 (19.7)u2005HU, p<0.001). Conclusion Greater baseline severity of CT-detected emphysema is related to lower baseline lung function and greater rates of lung function decline, even in those without airway obstruction. CT-detected emphysema aids in identifying non-obstructed male smokers who will develop airflow obstruction.

Presence of tumor-infiltrating lymphocytes is an independent prognostic factor in type I and II endometrial cancer

OBJECTIVEnPresence of tumor-infiltrating lymphocytes (TIL) is of prognostic importance in a variety of malignancies. This study aims to determine the prognostic value of CD8(+) cytotoxic T-lymphocytes (CTL), FoxP3(+) regulatory T-lymphocytes (Treg) and CD45R0(+) memory T-lymphocytes in endometrial cancer.nnnMETHODSnThe number of tumor-infiltrating CD8(+), FoxP3(+), and CD45R0(+) T-lymphocytes was determined by immunohistochemistry on tissue microarrays containing tumor material from 368 FIGO stage I-IV endometrial cancer patients. Results from immunohistochemistry were correlated with clinicopathological parameters and survival.nnnRESULTSnHigh numbers of intra-tumoral CD8(+) T-lymphocytes, a high CD8(+)/FoxP3(+) ratio and the presence of CD45R0(+) T-lymphocytes were strongly associated with well-known favorable prognostic factors in endometrial cancer. Furthermore, high numbers of CD8(+) T-lymphocytes and a high CD8(+)/FoxP3(+) ratio were associated with a better disease free survival (DFS). High numbers of CD8(+) T-lymphocytes and the presence of CD45R0(+) T-lymphocytes were associated with a prolonged overall survival (OS). In multivariate analysis, high numbers of CD8(+) T-lymphocytes had an independent prognostic impact for overall survival in the entire cohort (HR 0.48, 95% C.I. 0.26-0.89, p=0.019) and in type II endometrial cancer (HR 0.17, 95% C.I. 0.08-0.36, p<0.001). A high CD8(+)/FoxP3(+) ratio was independently associated with improved survival in type I endometrial cancer (HR 0.44, 95% C.I. 0.23-0.84, p=0.013). CD45R0(+) lymphocytes were an independent factor for improved OS (HR 0.42, 95% C.I. 0.19-0.93, p=0.033).nnnCONCLUSIONnThis study shows that the presence of TIL is an independent prognostic factor in endometrial cancer and indicates an important role for the immune system in endometrial cancer.

Chronic bronchitis sub-phenotype within COPD: inflammation in sputum and biopsies

The presence of chronic bronchitis predicts a more rapid decline of forced expiratory volume in one second (FEV1) in patients with chronic obstructive pulmonary disease (COPD). The hallmark of COPD is airway inflammation. It was hypothesised that COPD patients with chronic bronchitis are characterised by a distinct inflammatory cell profile, as measured in bronchial biopsies and sputum. From 114 COPD patients (male/female ratio 99/15, mean±sd age 62±8u2005yrs, current smoking 63%, post-bronchodilator FEV1 63±9% predicted, no steroids), with and without chronic bronchitis, inflammatory cell counts in bronchial biopsies and induced sputum were measured. Analysis was carried out by logistic regression. COPD patients with chronic bronchitis had lower eosinophil counts in biopsies and higher percentages of sputum eosinophils than patients without those symptoms, which remained after adjustment for smoking and sex. Patients with chronic bronchitis also showed higher percentages of macrophages and lower percentages of neutrophils in sputum, which could be explained by differences in smoking and sex. It was concluded that chronic bronchitis reflects an inflammatory sub-phenotype among patients with chronic obstructive pulmonary disease. The present results indicate a preferential distribution of eosinophils towards the airway lumen in patients with chronic bronchitis. This may have implications for anti-inflammatory treatment of chronic obstructive pulmonary disease patients with chronic bronchitis.

Perinatal predictors of respiratory symptoms and lung function at a young adult age

A longitudinal cohort of 2,957 babies, born in 1975–1978, was used to investigate whether perinatal factors predict respiratory morbidity at a young adult age. In 1997, the presence of asthmatic (wheeze, nocturnal dyspnoea) and bronchitic (cough, phlegm, dyspnoea grade 3) symptoms and the level of lung function was determined in this cohort. The independent association between smoking during pregnancy, being first-born, birth weight and respiratory symptoms and lung function at young adult age was investigated using multiple regression models, taking other potential risk factors into account. Of 1,568 responders, 608 (39%, aged 18–22u2005yrs) had at least one respiratory symptom. The young adults who had a mother that smoked during pregnancy had a significantly lower level of lung function than their nonintra-uterine exposed peers (regression coefficient (B) (standard error): peak expiratory flow (PEF) −0.257 (0.131) L·s−1; forced expiratory flow when 25% of the forced vital capacity has been exhaled (FEF25) −0.290 (0.129) L·s−1), although they were not at increased risk of having respiratory symptoms. Young adults who were first-born had better levels of lung function (B (se): forced expiratory volume in one second (FEV1) 0.090 (0.042) L) and were less likely to have asthmatic symptoms (odds ratio (95% confidence interval): 0.58 (0.35–0.95)) than those not first-born. Low birth weight (FEV1 −0.013 (0.004) L for a reduction of 100u2005g) was also predictive of reduced achieved levels of lung function at young adult age, independent of other potential risk factors, e.g. current smoking habits or familial predisposition. This study adds to the knowledge of the role of perinatal factors, such as smoking during pregnancy, as important predictors of respiratory morbidity.

Detection of telomerase, its components, and human papillomavirus in cervical scrapings as a tool for triage in women with cervical dysplasia

Aim: To examine whether the detection of either telomerase and its components or high risk human papillomavirus (HPV) are of value in predicting the presence of cervical intraepithelial neoplasia (CIN) grade II/III in women referred because of cervical cytology reports showing at most moderate dyskaryosis. Methods: Cervical scrapings of 50 women referred with cytological borderline, mild, or moderate dyskaryosis were analysed. Telomerase activity was assessed by a commercially available telomere repeat amplification protocol assay and its components human telomerase RNA (hTR) and human telomerase reverse transcriptase (hTERT) were assessed by reverse transcriptase polymerase chain reaction (PCR). HPV was detected by GP5+/6+ PCR enzyme immunosassay. Histological findings on colposcopy guided biopsies or excised cervical tissue were regarded as the final pathological diagnosis. The sensitivity and specificity for detecting CIN II/III were calculated. Results: Twenty eight women were diagnosed with CIN II/III. Telomerase activity was detected in none, hTR in 88%, hTERT in 23%, and high risk HPV was detected in 79% of these women. As a diagnostic test none of the described analyses combined a sensitivity of at least 90% with a specificity ≥ 90%. Despite the small numbers, calculation of the 95% confidence intervals excluded a combined sensitivity and specificity of at least 90% for all of the evaluated parameters. Conclusions: Neither detection of telomerase or its components, nor detection of high risk HPV seem suitable for the triage of women with borderline, mild, and moderate cytological dyskaryosis.

Pesticides and other occupational exposures are associated with airway obstruction: the LifeLines cohort study

Objectives Occupational exposures are important and possibly modifiable contributors to the global burden of chronic obstructive pulmonary disease (COPD). Exposure to vapours, gases, dusts and fumes (VGDF) has been associated with a two- to threefold higher COPD risk. Less is known about effects of occupational exposure to pesticides and solvents. In the current study, we assessed if VGDF, pesticides and solvents are associated with the level of lung function and the prevalence of airway obstruction in the general population. Methods We included 11u2005851 subjects aged 18–89u2005years from the LifeLines cohort study. Regression models assessing associations between occupational exposures (no/low/high), level of lung function (prebronchodilator FEV1, FEV1/FVC) and mild and moderate/severe airway obstruction were adjusted for sex, age, height, weight, current/ex-smoking and packyears. Additionally, we stratified by smoking status and gender and tested for interaction. A second general population cohort (n=2364) was used to verify our initial findings. Results Occupational exposure to VGDF and pesticides was associated with a lower level of FEV1 and FEV1/FVC and with a higher prevalence of mild and moderate/severe airway obstruction in the two general populations investigated. There were no associations with exposure to solvents. Conclusions Occupational exposure to both VGDF and pesticides is associated with airway obstruction in the general population.

Superoxide dismutases, lung function and bronchial responsiveness in a general population

Oxidative stress is an important causative factor in the onset and progression of smoking-related lung diseases, such as chronic obstructive pulmonary disease (COPD). Superoxide dismutases (SODs) can prevent an increase in oxidative burden. A total of 1,390 subjects from the prospective Vlagtwedde–Vlaardingen cohort were genotyped for two single nucleotide polymorphisms (SNPs) in SOD2 and four SNPs in SOD3, which were further analysed for associations with the presence of bronchial hyperresponsiveness (BHR; provocative concentration causing a 10% fall in the forced expiratory volume in one second (FEV1; PC10 ≤8u2005mg·mL−1 of histamine), COPD (defined as Global Initiative for Chronic Obstructive Lung Disease stage II or higher), lung function level and the longitudinal course of FEV1. The intronic C5774T SNP of SOD2 was significantly associated with the presence of COPD and BHR in the total population. The T/T genotype for this polymorphism and the Val/Val genotype for the SOD2 Ala16Val substitution were risk factors for BHR in individuals without COPD. The SOD3 Arg213Gly substitution was associated with slower FEV1 decline in never-smokers exclusively, and the SOD3 G(−4466)T SNP was associated with a lower vital capacity level. Both SOD2 polymorphisms are associated with bronchial hyperresponsiveness, a risk factor for chronic obstructive pulmonary disease, while SOD2 C5774T additionally confers a risk for chronic obstructive pulmonary disease in the total population. The current authors furthermore confirm previously reported associations of SOD3 single nucleotide polymorphisms with lung function in the general population.

Identification of genes and pathways associated with cytotoxic T lymphocyte infiltration of serous ovarian cancer

Background:Tumour-infiltrating lymphocytes (TILs) are predictors of disease-specific survival (DSS) in ovarian cancer. It is largely unknown what factors contribute to lymphocyte recruitment. Our aim was to evaluate genes and pathways contributing to infiltration of cytotoxic T lymphocytes (CTLs) in advanced-stage serous ovarian cancer.Methods:For this study global gene expression was compared between low TIL (n=25) and high TIL tumours (n=24). The differences in gene expression were evaluated using parametric T-testing. Selectively enriched biological pathways were identified with gene set enrichment analysis. Prognostic influence was validated in 157 late-stage serous ovarian cancer patients. Using immunohistochemistry, association of selected genes from identified pathways with CTL was validated.Results:The presence of CTL was associated with 320 genes and 23 pathways (P<0.05). In addition, 54 genes and 8 pathways were also associated with DSS in our validation cohort. Immunohistochemical evaluation showed strong correlations between MHC class I and II membrane expression, parts of the antigen processing and presentation pathway, and CTL recruitment.Conclusion:Gene expression profiling and pathway analyses are valuable tools to obtain more understanding of tumour characteristics influencing lymphocyte recruitment in advanced-stage serous ovarian cancer. Identified genes and pathways need to be further investigated for suitability as therapeutic targets.