On the basis of morphological features, we subclassified 189 intrahepatic cholangiocarcinomas into two subtypes: bile duct and cholangiolar. The cholangiolar type is composed of cuboidal to low columnar tumor cells that contain scanty cytoplasm. The bile duct type is composed of tall columnar tumor cells arranged in a large glandular pattern. In this study, 77 (41%) tumors were classified as the cholangiolar type and 112 (59%) tumors were classified as the bile duct type. The cholangiolar-type intrahepatic cholangiocarcinoma was more frequently associated with viral hepatitis, whereas all but one intrahepatic cholangiocarcinoma associated with intrahepatic lithiasis were classified as the bile duct type. Biliary intraepithelial neoplasm or intraductal papillary neoplasm of the bile duct could be identified in 50 bile duct-type intrahepatic cholangiocarcinomas (45%), but in only 3 cholangiolar-type intrahepatic cholangiocarcinomas (4%). Cholangiolar-type intrahepatic cholangiocarcinomas frequently expressed N-cadherin, whereas bile duct intrahepatic cholangiocarcinomas were more likely to express S100P, Trefoil factor 1, and anterior gradient 2. KRAS is mutated in 23 of 98 (23%) bile duct-type intrahepatic cholangiocarcinomas and in only 1 of 76 (1%) cholangiolar-type intrahepatic cholangiocarcinomas. Cholangiolar-type intrahepatic cholangiocarcinomas had a higher frequency of IDH1 or 2 mutations than did the bile duct-type intrahepatic cholangiocarcinomas. The molecular features of the bile duct-type intrahepatic cholangiocarcinoma were similar to those of hilar cholangiocarcinoma. Patients with the cholangiolar-type intrahepatic cholangiocarcinoma had higher 5-year survival rates than those of patients with the bile duct-type intrahepatic cholangiocarcinoma. Our results indicated that intrahepatic cholangiocarcinoma was a heterogeneous tumor. Subclassification of intrahepatic cholangiocarcinomas based on cholangiocytic differentiation divides them into two groups with different etiologies, clinical manifestations, and molecular pathogeneses.

We quantify the morphologies and dynamical states of 59 galaxy clusters using the power-ratio technique of Buote & Tsai applied to ROSAT PSPC X-ray images.The clusters exhibit a particularly strong P 2 =P 0 P 4 =P 0 correlation in the 1h 1 80 Mpc aperture which may be interpreted as an evolutionary track; the location of a cluster on the correlation line indicates the dynamical state of the cluster and the distribution of clusters along this track measures the rate of formation and evolution of clusters in our sample. The power ratios anti-correlate with the cooling-ow rate indicating a reasonable dependence of the ow rate on cluster morphology. The relationship of the power ratios to the optical Bautz-Morgan (BM) Type is more complex. This is because the power ratios are sensitive to unrelaxed regions of clusters within a speci ed scale, whereas BM types are sensitive to unrelaxed regions over many scales. We discuss further astrophysical applications exploiting the relationship between the power ratios and the evolutionary states of clusters. { 2 {From these qualitative measures of \frequency of substructure" in clusters, investigators have attempted to determine (e.g., Richstone et al. 1992) and the power spectrum of primordial density uctuations (e.g., David et al. 1993) by comparison to Press-Schechter (1974) type predictions of the distribution of collapsed (i.e. virialized) objects. However, these comparisons are inherently uncertain because of the unknown relationship between a particular investigator's de nition of \substructure" and the dynamical state of a cluster. Even well de ned and quantitative measures of morphology which employ centroid-shifts and axial ratios (Evrard et al. 1993, Mohr et al. 1995 do not clearly provide any physical connection of these parameters to the dynamical states of clusters.We previously presented a method to quantify the morphologies of galaxy clusters in relation to their dynamical states as given by their gravitational potentials (Buote & Tsai 1995b; hereafter BT). The statistics of this method, i.e. \power ratios", in essence measure the square of the ratio of higher-order multipole moments of the two-dimensional potential to the monopole moment. The power-ratio description of the morphologies of X-ray clusters is intended to classify structure that is obvious to the eye, not subtle substructure that requires more robust techniques (e.g., Bird & Beers 1993); i.e. the signi cance of the substructure is a given, what the structure implies for the aggregate cluster dynamics is our concern.Because of their intimate link to cluster dynamics, power ratios are not only ideal for cosmological studies, but also for studies of clusters themselves. It is our purpose in this paper to create a database of power ratios for testing the predictions of various cosmogonies and to present initial results on the implications of the measured power ratios. We discuss the cluster sample in x2 and the data reduction and analysis in x3. We consider correlations of the various power ratios amo...

We describe and test a method to quantitatively classify clusters of galaxies according to their projected morphologies. This method will be subsequently used to place constraints on cosmological parameters ( and the power spectrum of primordial uctuations on scales at or slightly smaller than that of clusters) and to test theories of cluster formation. We speci cally address structure that is easily discernible in projection and dynamically important to the cluster. The method is derived from the two-dimensional multipole expansion of the projected gravitational potential and yields dimensionless power ratios as morphological statistics. If the projected mass pro le is used to characterize the cluster morphology, the power ratios are directly related to the cluster potential. However, since detailed mass pro les currently exist for only a few clusters, we use the X-ray{emitting gas as an alternative tracer of cluster morphology. In this case, the relation of the power ratios to the potential is qualitatively preserved. We demonstrate the feasibility of the method by analyzing simulated observations of simple models of X-ray clusters using the instrument parameters of the ROSAT PSPC. For illustrative purposes, we apply the method to ROSAT PSPC images of A85, A514, A1750, and A2029. These clusters, which di er substantially in their X-ray morphologies, are easily distinguished by their respective power ratios. We discuss the suitability of this method to address the connection between cluster morphology and cosmology and to assess whether an individual cluster is su ciently relaxed for analysis of its intrinsic shape using hydrostatic methods. Approximately 50 X-ray observations of Abell clusters with the PSPC will be amenable to morphological analysis using the method of this paper.

Traditional serrated adenoma is one type of colorectal serrated neoplasm and a precursor of colorectal cancer. We evaluated the pathologic and molecular features of 60 traditional serrated adenomas with cytologic dysplasia and/or invasive carcinoma. On the basis of morphological features, 16 cases (27%) were categorized as traditional serrated adenoma with serrated dysplasia and 25 cases (42%) as traditional serrated adenoma with conventional adenomatous dysplasia. In addition, 19 cases (31%) showed an overall tubulovillous adenomatous structure but with focal serrated feature. Traditional serrated adenoma with serrated dysplasia had a significantly higher frequency of BRAF mutation than traditional serrated adenoma with conventional adenomatous dysplasia and tubulovillous adenoma with serrated feature (P ¼ 0.006), whereas traditional serrated adenoma with conventional adenomatous dysplasia and tubulovillous adenoma with serrated feature had higher frequencies of KRAS mutation than traditional serrated adenoma with serrated dysplasia (Po0.0001). Only traditional serrated adenoma with serrated dysplasia showed sessile serrated adenoma-like lesions at the periphery (n ¼ 3) and developed invasive carcinomas when the lesions were o15 mm in size. Abnormal nuclear accumulation of b-catenin was detected in traditional serrated adenoma with conventional adenomatous dysplasia and tubulovillous adenoma with serrated feature but not in traditional serrated adenoma with serrated dysplasia. The frequency of the positive CpG island methylator phenotype was similar among the three dysplastic subtypes, and immunostaining of four mismatch repair proteins in the nucleus was retained in all traditional serrated adenomas and associated invasive malignancies. Traditional serrated adenoma-associated adenocarcinomas (n ¼ 28) displayed distinctive morphological features: oval cell nuclei, serrated glands, infiltrating borders, rare occurrences of necrosis and mucinous differentiation. Overexpression of p53 was detected only in high-grade dysplasia and invasive adenocarcinoma. Our findings indicate that traditional serrated adenoma is a heterogeneous neoplasm with two pathways of neoplastic progression, which are distinct from the sessile serrated pathway of colorectal carcinogenesis.

We reexamine both numerically and analytically the collapse of the singular isothermal sphere in the context of low-mass star formation.We consider the case where the onset of collapse is initiated by some arbitrary process which is accompanied by a central output of either heat or kinetic energy. We find two classes of numerical solutions describing this manner of collapse. The first approaches in time the expansion wave solution of Shu, while the second class is characterized by an ever-decreasing central accretion rate and the presence of an outwardly propagating weak shock. The collapse solution which represents the dividing case between these two classes is determined analytically by a similarity analysis. This solution shares with the expansion wave solution the properties that the gas remains stationary with an r-2 density profile at large radius and that, at small radius, the gas free-falls onto a nascent core at a constant rate which depends only on the isothermal sound speed. This accretion rate is a factor of _0.1 that predicted by the expansion wave solution_ This reduction is due in part to the presence of a weak shock which propagates outward at 1.26 times the sound speed. Gas in the postshock region first moves out subsonically but is then decelerated and begins to collapse. The existence of two classes of numerical collapse solutions is explained in terms of the instability to radial perturbations of the analytic solution. Collapse occurring in the manner described by some of our solutions would eventually unbind a finite-sized core. However, this does not constitute a violation of the instability properties of the singular isothermal sphere which is unstable both to collapse and to expansion. To emphasize this, we consider a purely expanding solution for isothermal spheres. This solution is found to be self-similar and results in a uniform density core in the central regions of the gas. Our solutions may be relevant to the "luminosity" problem of protostellar cores since the predicted central accretion rates are significantly reduced relative to that of the expansion wave solution. Furthermore, our calculations indicate that star-forming cloud cores are not very tightly bound and that modest disturbances can easily result in both termination of infall and dispersal of unaccreted material.

We consider the lifecycle of dust introduced into the hot interstellar medium in isolated elliptical galaxies. Dust grains are ejected into galactic-scale cooling flows in large ellipticals by normal mass loss from evolving red giants. Newly introduced dust rapidly enters the hot gas environment and is sputtered away by thermal collisions with ions. Before the grains are completely sputtered away, they emit prodigious amounts of infrared radiation which may contribute to the large far infrared luminosities observed in ellipticals. In order to study the global properties of grains in ellipticals we construct a new series of King-type galactic models which are consistent with the fundamental plane, galactic mass to light ratios and other relevant observational correlations. We describe a new ``continuity'' procedure to construct simple time-dependent gas dynamic models for cooling flows. In all galaxy models, although grains can flow a considerable distance from their radius of origin before being sputtered away, the grain size distribution is accurately determined by assuming {\it in situ} sputtering, completely ignoring advection. The dominant source of grain heating is absorption of starlight; grain heating by collisions with energetic thermal electrons or X-ray absorption are negligible. However, we also show that when self-consistent grain sputtering is included the dust-to-gas ratio is reduced and radiative cooling, not electron-grain interactions dominates plasma cooling, even for the most massive ellipticals.Comment: 30 pages plain TeX, figures available by request to tsai@cita.utoronto.ca, to appear in ApJ

Leiomyosarcoma is an aggressive soft tissue sarcoma with poor patient survival. Recently, it was shown that 53% to 62% of leiomyosarcomas use the alternative lengthening of telomeres (ALT) as their telomere maintenance mechanism. The molecular basis of this mechanism has not been elucidated. Studies of pancreatic neuroendocrine tumor have suggested that the inactivation of either α-thalassemia/mental retardation syndrome X-linked (ATRX) or death domain-associated (DAXX) protein is associated with the ALT phenotype. In this study, we sought to determine the clinicopathologic features of leiomyosarcoma with the ALT phenotype and the possible relationship between this phenotype and ATRX/DAXX expression. Telomerase reverse transcriptase gene (TERT) promoter mutation analysis was also performed. Ninety-two leiomyosarcomas derived from the uterus, retroperitoneum/intra-abdomen, and various other sites were analyzed. Telomere-specific fluorescence in situ hybridization revealed that 59% (51/86) of leiomyosarcomas had the ALT phenotype. Loss of ATRX expression was observed in 33% of the tumors (30/92), and all but 2 ATRX-deficient tumors were ALT positive. Both the ALT phenotype and loss of ATRX expression were associated with epithelioid/pleomorphic cell morphology, tumor necrosis, and poor differentiation. None of the 92 cases lost DAXX expression. No TERT promoter mutation was detected (n=39). For survival analysis, poor differentiation, high FNCLCC grade, tumor size, and ALT phenotype were correlated with poor overall survival in univariate analysis. Tumor size and ALT phenotype remained independent prognostic factors in multivariate analysis. We concluded that the ALT phenotype in the leiomyosarcoma is associated with aggressive histologic features, loss of ATRX expression, and poor clinical outcome.

Using the simulation of Katz & White (1993) we have tested the viability of X-ray analysis for constraining the intrinsic shapes of clusters of galaxies considering the e ects of both substructure and steep temperature gradients. We restrict our analysis to the aggregate shapes of clusters on scales of r 1 2 Mpc in order to reduce our sensitivity to subclustering in the core. For low redshifts (z < 0:25) the X-ray method accurately measures the true ellipticity of the three-dimensional cluster dark matter provided the inclination of the cluster is known to within 30 ; assuming the gas is isothermal adds only small errors to the derived shapes. At higher redshifts the X-ray method yields unreliable results since the gas does not trace the cluster gravitational potential. We pro er some necessary conditions for the reliability of X-ray methods characterized by both the amount of substructure in the X-ray surface brightness images and the shapes of the isophotes. We conclude that measurements of the aggregate shapes of clusters on scales r 1 2 Mpc are insensitive to core substructure representing scales of a few hundred kpc. Therefore our results suggest that the X-ray measurements of aggregate cluster shapes by Fabricant, Rybicki, & Gorenstein (1984) and Buote & Canizares (1992) are valid provided that they do not su er from serious projection e ects. A substantial number of Abell clusters observed with the ROSAT PSPC will be amenable to X-ray shape analysis. 1 dbuote@space.mit.edu 2 jcht@cloud9.arc.nasa.gov