A laboratory-based scoring system predicts early treatment in Rai 0 chronic lymphocytic leukemia

We present a laboratory-based prognostic calculator (designated CRO score) to risk stratify treatment-free survival in early stage (Rai 0) chronic lymphocytic leukemia developed using a training-validation model in a series of 1,879 cases from Italy, the United Kingdom and the United States. By means of regression analysis, we identified five prognostic variables with weighting as follows: deletion of the short arm of chromosome 17 and unmutated immunoglobulin heavy chain gene status, 2 points; deletion of the long arm of chromosome 11, trisomy of chromosome 12, and white blood cell count>32.0x103/microliter, 1 point. Low, intermediate and high-risk categories were established by recursive partitioning in a training cohort of 478 cases, and then validated in four independent cohorts of 144/395/540/322 cases, as well as in the composite validation cohort. Concordance indices were 0.75 in the training cohort and ranged from 0.63 to 0.74 in the four validation cohorts (0.69 in the composite validation cohort). These findings advocate potential application of our novel prognostic calculator to better stratify early-stage chronic lymphocytic leukemia, and aid case selection in risk-adapted treatment for early disease. Furthermore, they support immunocytogenetic analysis in Rai 0 chronic lymphocytic leukemia being performed at the time of diagnosis to aid prognosis and treatment, particularly in today's chemo-free era

Detectable clonal mosaicism and its relationship to aging and cancer

In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of >2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 × 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 × 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases

Improved regression calibration

The likelihood for generalized linear models with covariate measurement error cannot in general be expressed in closed form which makes maximum likelihood estimation taxing. A popular alternative is regression calibration which is computationally efficient at the cost of inconsistent estimation. We propose an improved regression calibration approach, a general pseudo maximum likelihood estimation method based on a conveniently decomposed form of the likelihood. It is both consistent and computationally efficient, and produces point estimates and estimated standard errors which are practically identical to those obtained by maximum likelihood. Simulations suggest that improved regression calibration which is easy to implement in standard software, works well in a range of situations

A RANDOMISED CONTROLLED TRIAL COMPARING COMBINED EBUS/EUS FOLLOWED BY SURGICAL STAGING VERSUS SURGICAL STAGING ALONE IN NON-SMALL CELL LUNG CANCER: THE ASTER STUDY

Diabetes mellitus: pathophysiological changes and therap

Generalized multilevel structural equation modeling

multilevel structural equation models, generalized linear mixed models, latent variables, random effects, hierarchical models, item response theory, factor models, adaptive quadrature, empirical Bayes, GLLAMM,

EUS-FNA for the detection of left adrenal metastasis in patients with lung cancer

Item does not contain fulltextIn patients with lung cancer, enlarged or (18)Fluoro-deoxyglucose positron emission tomography ((18)FDG-PET) positive left adrenal glands are suspected for distant metastases and require tissue confirmation for a definitive assessment. The aim of this study was to assess the sensitivity of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) for left adrenal metastases in lung cancer patients with a suspect adrenal gland based on imaging. EUS-FNA findings of patients with (suspected) lung cancer and CT enlarged or (18)FDG-PET positive left adrenal glands were retrospectively evaluated. In the absence of metastases at EUS, clinical and radiological follow-up was obtained. In 85 patients, EUS-FNA demonstrated left adrenal metastases of lung cancer in 53 (62%), benign adrenal tissue in 25 (29%), a metastasis from colon carcinoma in 1 (1%) and a primary adrenocortical carcinoma in 1 (1%) patient. In five patients (5.9%), the aspirates contained non-representative material. EUS outcomes were false negative in two patients. Sensitivity and negative predictive value (NPV) for EUS-FNA of the left adrenal gland were at least 86% (95% CI 74-93%) and 70% (95% CI 50-85%). No complications occurred. EUS-FNA is a sensitive, safe and minimally invasive technique to provide tissue proof of left adrenal metastases in patients with (suspected) lung cancer and enlarged or (18)FDG-PET positive adrenal glands. Therefore, EUS-FNA qualifies as the staging test of choice for patients with lung cancer with suspected left adrenal metastases

Mediastinoscopy vs Endosonography for Mediastinal Nodal Staging of Lung Cancer A Randomized Trial

Context Mediastinal nodal staging is recommended for patients with resectable non-small cell lung cancer (NSCLC). Surgical staging has limitations, which results in the performance of unnecessary thoracotomies. Current guidelines acknowledge minimally invasive endosonography followed by surgical staging (if no nodal metastases are found by endosonography) as an alternative to immediate surgical staging. Objective To compare the 2 recommended lung cancer staging strategies. Design, Setting, and Patients Randomized controlled multicenter trial (Ghent, Leiden, Leuven, Papworth) conducted between February 2007 and April 2009 in 241 patients with resectable (suspected) NSCLC in whom mediastinal staging was indicated based on computed or positron emission tomography. Intervention Either surgical staging or endosonography (combined transesophageal and endobronchial ultrasound [EUS-FNA and EBUS-TBNA]) followed by surgical staging in case no nodal metastases were found at endosonography. Thoracotomy with lymph node dissection was performed when there was no evidence of mediastinal tumor spread. Main Outcome Measures The primary outcome was sensitivity for mediastinal nodal (N2/N3) metastases. The reference standard was surgical pathological staging. Secondary outcomes were rates of unnecessary thoracotomy and complications. Results Two hundred forty-one patients were randomized, 118 to surgical staging and 123 to endosonography, of whom 65 also underwent surgical staging. Nodal metastases were found in 41 patients (35%; 95% confidence interval [CI], 27%-44%) by surgical staging vs 56 patients (46%; 95% CI, 37%-54%) by endosonography (P=.11) and in 62 patients (50%; 95% CI, 42%-59%) by endosonography followed by surgical staging (P=.02). This corresponded to sensitivities of 79% (41/52; 95% CI, 66%-88%) vs 85% (56/66; 95% CI, 74%-92%) (P=.47) and 94% (62/66; 95% CI, 85%-98%) (P=.02). Thoracotomy was unnecessary in 21 patients (18%; 95% CI, 12%-26%) in the mediastinoscopy group vs 9 (7%; 95% CI, 4%-13%) in the endosonography group (P=.02). The complication rate was similar in both groups. Conclusions Among patients with (suspected) NSCLC, a staging strategy combining endosonography and surgical staging compared with surgical staging alone resulted in greater sensitivity for mediastinal nodal metastases and fewer unnecessary thoracotomies. Trial Registration clinicaltrials.gov Identifier: NCT00432640 JAMA. 2010;304(20):2245-2252 www.jama.comPathogenesis and treatment of chronic pulmonary disease

Parent of origin effects on age at colorectal cancer diagnosis

Genomic imprinting refers to a parent-of-origin specific effect on gene expression. At least 1% of genes in the human genome are modulated in this manner. We sought evidence for genomic imprinting in colorectal cancer by studying the ages at diagnosis in the offspring of 2,061 parent-child pairs in which both parent and child were affected by nonsyndromic colorectal cancer. Families were ascertained through the colon Cancer Family Registry [http://epi.grants.cancer.gov/CFR/] from both population-based and clinic-based sources. We found that the affected offspring of affected fathers were on average younger than offspring of affected mothers (55.8 vs. 53.7 years; p = 0.0003), but when divided into sons and daughters, this difference was driven entirely by younger age at diagnosis in daughters of affected fathers compared to sons (52.3 years vs. 55.1 years; p = 0.0004). A younger age at diagnosis in affected daughters of affected fathers was also observable in various subsets including families that met Amsterdam II Criteria, families that did not meet Amsterdam Criteria, and in families with documented normal DNA mismatch repair in tumors. Imprinting effects are not expected to be affected by the sex of the offspring. Possible explanations for these unexpected findings include: (i) an imprinted gene on the pseudoautosomal regions of the X chromosome; (ii) an imprinted autosomal gene that affects a sex-specific pathway; or (iii) an X-linked gene unmasked because of colonic tissue-specific preferential inactivation of the maternal X chromosome.Noralane M. Lindor, Kari G. Rabe, Gloria M. Petersen, Helen Chen, Bharati Bapat, John Hopper, Joanne Young, Mark Jenkins, John Potter, Polly Newcomb, Allyson Templeton, Loic LeMarchand, John Grove, Michael R. Burgio, Robert Haile, Jane Green, Michael O. Woods, Daniela Seminara, Paul J. Limburg, and Stephen N. Thibodea

Endosonography vs conventional bronchoscopy for the diagnosis of sarcoidosis: the GRANULOMA randomized clinical trial

Item does not contain fulltextIMPORTANCE: Tissue verification of noncaseating granulomas is recommended for the diagnosis of sarcoidosis. Bronchoscopy with transbronchial lung biopsies, the current diagnostic standard, has moderate sensitivity in assessing granulomas. Endosonography with intrathoracic nodal aspiration appears to be a promising diagnostic technique. OBJECTIVE: To evaluate the diagnostic yield of bronchoscopy vs endosonography in the diagnosis of stage I/II sarcoidosis. DESIGN, SETTING, AND PATIENTS: Randomized clinical multicenter trial (14 centers in 6 countries) between March 2009 and November 2011 of 304 consecutive patients with suspected pulmonary sarcoidosis (stage I/II) in whom tissue confirmation of noncaseating granulomas was indicated. INTERVENTIONS: Either bronchoscopy with transbronchial and endobronchial lung biopsies or endosonography (esophageal or endobronchial ultrasonography) with aspiration of intrathoracic lymph nodes. All patients also underwent bronchoalveolar lavage. MAIN OUTCOMES AND MEASURES: The primary outcome was the diagnostic yield for detecting noncaseating granulomas in patients with a final diagnosis of sarcoidosis. The diagnosis was based on final clinical judgment by the treating physician, according to all available information (including findings from initial bronchoscopy or endosonography). Secondary outcomes were the complication rate in both groups and sensitivity and specificity of bronchoalveolar lavage in the diagnosis of sarcoidosis. RESULTS: A total of 149 patients were randomized to bronchoscopy and 155 to endosonography. Significantly more granulomas were detected at endosonography vs bronchoscopy (114 vs 72 patients; 74% vs 48%; P < .001). Diagnostic yield to detect granulomas for endosonography was 80% (95% CI, 73%-86%); for bronchoscopy, 53% (95% CI, 45%-61%) (P < .001). Two serious adverse events occurred in the bronchoscopy group and 1 in the endosonography group; all patients recovered completely. Sensitivity of the bronchoalveolar lavage for sarcoidosis based on CD4/CD8 ratio was 54% (95% CI, 46%-62%) for flow cytometry and 24% (95% CI, 16%-34%) for cytospin analysis. CONCLUSION AND RELEVANCE: Among patients with suspected stage I/II pulmonary sarcoidosis undergoing tissue confirmation, the use of endosonographic nodal aspiration compared with bronchoscopic biopsy resulted in greater diagnostic yield. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00872612