Clinicopathological and molecular characterization of gastroesophageal junction (GEJ) adenocarcinoma before age of 40 years

Gastroesophageal junction (GEJ) adenocarcinoma are uncommon before age of 40 years. While certain clinical, pathological and molecular features of GEJ adenocarcinoma in older patients have been extensively studied, these characteristics in the younger population remain to be determined. In the recent literature, a high sensitivity and specificity for the detection of dysplasia and esophageal adenocarcinoma was demonstrated by using multicolor fluorescence in situ hybridization (FISH) DNA probe set specific for the locus specific regions 9p21 (p16), 20q13.2 and Y chromosome. We evaluated 663 patients with GEJ adenocarcinoma and further divided them into 2 age-groups of or= 50 years, rispectively. FISH with selected DNA probe for Y chromosome, locus 9p21 (p16), and locus 20q13.2 was investigated with formalin fixed and parassin embedded tissue from surgical resections of 17 younger and 11 older patients. Signals were counted in > 100 cells with each given histopathological category. The chromosomal aberrations were then compared in the 2 age-groups with the focus on uninvolved squamous and columnar epithelium, intestinal metaplasia (Barrett's mucosa), glandular dysplasia, and adenocarcinoma. Comparisons were performed by the X2 test, Fisher's exact test, Student's t-test and Mann-Whitney U-test as appropriate. Survival was estimated by the Kaplan-Meier method with univariate analysis by the log-rank. Significance was taken at the 5% level. There was no difference in the surgical technique applied in both age groups and most patients underwent Ivor Lewis esophagectomy. Among clinical variables there was a higher incidence of smocking history in older patient group. We identified a progressive loss of Y chromosome from benign squamos epithelium to Barrett's mucosa and glandular dysplasia, and, ultimately, to a near complete loss in adenocarcinoma in both age groups. The young group revealed significantly more losses of 9p21 in both benign and neoplastic cells when compared to the older patients group. In addition, we demonstrated an increase in the percentage of cells showing gain of locus 20q13.2 with progression from benign epithelium through dysplasia to adenocarcinoma with almost the same trend in both the young and the older patients. When compared with the older age-group, younger patients with GEJ adenocarcinoma possess similar known demographics, environmental factors, clinical, and pathologic characteristics. The most commonly detected genetic aberrations of progressive Y chromosomal loss, 9p21 locus loss, and 20q13 gains were similar in the younger and older patients. However the rate of loss of 9p21 is significantly higher in young patients, in both the benign and the neoplastic cells. The loss of 9p21, and possibly, the subsequent inactivation of p16 gene may be one of the molecular mechanisms responsible for the accelerated neoplastic process in young patients.

The Universe 10 Billion years ago: Morphologies, Star-formation rates and Galactic-scale winds in z ∼ 2 Galaxies

This thesis is devoted to the study of the properties of high-redsfhit galaxies in the epoch 1 < z < 3, when a substantial fraction of galaxy mass was assembled, and when the evolution of the star-formation rate density peaked. Following a multi-perspective approach and using the most recent and high-quality data available (spectra, photometry and imaging), the morphologies and the star-formation properties of high-redsfhit galaxies were investigated. Through an accurate morphological analyses, the built up of the Hubble sequence was placed around z ~ 2.5. High-redshift galaxies appear, in general, much more irregular and asymmetric than local ones. Moreover, the occurrence of morphological k-­correction is less pronounced than in the local Universe. Different star-formation rate indicators were also studied. The comparison of ultra-violet and optical based estimates, with the values derived from infra-red luminosity showed that the traditional way of addressing the dust obscuration is problematic, at high-redshifts, and new models of dust geometry and composition are required. Finally, by means of stacking techniques applied to rest-frame ultra-violet spectra of star-forming galaxies at z~2, the warm phase of galactic-scale outflows was studied. Evidence was found of escaping gas at velocities of ~ 100 km/s. Studying the correlation of inter-­stellar absorption lines equivalent widths with galaxy physical properties, the intensity of the outflow-related spectral features was proven to depend strongly on a combination of the velocity dispersion of the gas and its geometry.