This US study was conducted to determine whether mode of diagnosis and initial disease presentation influence lung disease and survival in patients with cystic fibrosis. The study population included 27,703 patients reported to the 1986-2000 Cystic Fibrosis Foundation Registry. Patients were segregated into four diagnostic categories: meconium ileus (MI), prenatal/neonatal screening (SCREEN), positive family history (FH), and symptoms other than meconium ileus (SYMPTOM). When compared with patients in the SCREEN group, those in the MI or SYMPTOM group were found to have significantly greater risks of shortened survival, Pseudomonas aeruginosa acquisition, and forced expiratory volume in 1 second (FEV(1)) below 70% of predicted. In the SYMPTOM group, the greatest risks of shortened survival, P. aeruginosa acquisition, and FEV(1) <70% occurred for patients presenting with combined respiratory and gastrointestinal symptoms, followed by respiratory or gastrointestinal symptoms alone; the best outcomes were in patients with other presenting features. Additionally, patients with presumably "severe" genotypes (DeltaF508 plus other class I, II, III mutations in both alleles) had greater risks of shortened survival and P. aeruginosa acquisition compared with patients with presumably "mild" genotypes (class IV or V mutations in one or both alleles).

Telomeres protect against chromosomal breakage, fusion, and interchromosome bridges during cell division. Shortened telomeres have been observed in the lowest grade of pancreatic intraepithelial neoplasia. Genetically engineered mouse models of pancreatic neoplasia develop acinar-to-ductal metaplasia prior to the development of pancreatic intraepithelial neoplasia suggesting that acinar-to-ductal metaplasias can be an early precursor lesion to pancreatic cancer. Some human pancreatic intraepithelial neoplasias are associated with acinar-to-ductal metaplasias, and it has been suggested that these acinar-to-ductal metaplasias arise as a consequence of growth of adjacent pancreatic intraepithelial neoplasias. Since the earliest known genetic lesions of pancreatic intraepithelial neoplasias is shortened telomeres we compared the telomere lengths of acinar-to-ductal metaplasia lesions, pancreatic intraepithelial neoplasias and adjacent normal cells of human pancreata to determine if acinar-to-ductal metaplasias could be precursors to pancreatic intraepithelial neoplasia. We used quantitative fluorescent in situ hybridization to measure the telomere length of cells from pancreatic lesions and adjacent normal pancreata from 22 patients, including 20 isolated acinar-to-ductal metaplasias, 13 pancreatic intraepithelial neoplasias associated with acinar-to-ductal metaplasias, and 12 pancreatic intraepithelial neoplasias. Normalized mean telomere fluorescence was significantly different among the cell types analyzed; 12.6±10.2 units in normal acinar cells, 10.2±6.4 in ductal cells, 8.4±5.9 in fibroblasts, 9.4±7.3 in isolated acinar-to-ductal metaplasias, 4.1±2.9 in pancreatic intraepithelial neoplasia-associated acinar-to-ductal metaplasias, and 1.6±1.9 in pancreatic intraepithelial neoplasias, respectively (p<0.001, ANOVA with randomized block design). Telomeres were significantly shorter in pancreatic intraepithelial neoplasia-associated acinar-to-ductal metaplasias (p<0.05, post-hoc Duncan test) and in pancreatic intraepithelial neoplasias (p<0.05), than in normal cells, or isolated acinar-to-ductal metaplasias. Thus, shortened telomeres are found in pancreatic intraepithelial neoplasia-associated acinar-to-ductal metaplasias, but not in isolated acinar-to-ductal metaplasia lesions. These results indicate that isolated acinar-to-ductal metaplasias are not a precursor to pancreatic intraepithelial neoplasia, and support the hypothesis that pancreatic intraepithelial neoplasia-associated acinar-to-ductal metaplasias arise secondary to pancreatic intraepithelial neoplasia lesions.

The choice of therapy for metastatic cancer is largely empirical because of a lack of chemosensitivity prediction for available combination chemotherapeutic regimens. Here, we identify molecular models of bladder carcinoma chemosensitivity based on gene expression for three widely used chemotherapeutic agents: cisplatin, paclitaxel, and gemcitabine. We measured the growth inhibition elicited by these three agents in a series of 40 human urothelial cancer cell lines and correlated the GI 50 (50% of growth inhibition) values with quantitative measures of global gene expression to derive models of chemosensitivity using a misclassification-penalized posterior approach. The misclassification-penalized posteriorderived models predicted the growth response of human bladder cancer cell lines to each of the three agents with sensitivities of between 0.93 and 0.96. We then developed an in silico approach to predict the cellular growth responses for each of these agents in the clinically relevant two-agent combinations. These predictions were prospectively evaluated on a series of 15 randomly chosen bladder carcinoma cell lines. Overall, 80% of the predicted combinations were correct (P = 0.0002). Together, our results suggest that chemosensitivity to drug combinations can be predicted based on molecular models and provide the framework for evaluation of such models in patients undergoing combination chemotherapy for cancer. If validated in vivo, such predictive models have the potential to guide therapeutic choice at the level of an individual's tumor.