Lymphovascular Invasion in Colorectal Cancer: An Interobserver Variability Study

Background: Lymphovascular invasion (LVI) in colorectal cancer (CRC) is considered a strong stage-independent prognostic factor and influences decisions regarding adjuvant chemotherapy in patients with Stage II tumors. However, the degree of interobserver agreement among pathologists for LVI in CRC is largely unknown. This study was undertaken to examine such interobserver variability, and we hypothesized that the use of immunohistochemical markers for vascular and lymphatic channels could improve interobserver agreement. Design: Fifty cases of AJCC stage II moderately differentiated CRC from 1990 to 2005 from the pathology archives were selected; mucinous, medullary, and other recognized special subtypes were excluded. Fifty H&E slides (one from each case) were circulated to 6 GI pathologists, who independently assessed small and large vessel invasion. No diagnostic guidelines were given to the participating pathologists; each was instructed to apply the criteria for LVI that he or she used in daily practice. Immunohistochemistry (IHC) for D2-40 and CD31 was performed on corresponding paraffin blocks. The IHC slides were randomized, recirculated, and rescored for LVI. Results were analyzed by kappa (κ)statistics, which correct for agreement by chance, and for percent agreement. Results: The average κ values were determined for the H&E slides (large and small vessel), CD31 (small vessel), and D2-40 (small vessel) (Figure 1). Agreement was fair for H&E small vessel invasion (κ = 0.28; 95%CI 0.22–0.34). The least agreement was seen in interpretation of H&E large vessel invasion (κ = 0.18; 95%CI 0.11–0.26). Agreement was not improved by use of immunohistochemical stains: CD31 (large vessel, κ = 0.42, 95%CI 0.20–0.63, small vessel, κ = 0.26, 95%CI 0.10–0.42) and D2-40 (κ = 0.32, 95%CI 0.21–0.42). Conclusions: Interobserver variability in diagnosis of LVI was substantial on H&E slides and did not improve upon use of IHC. Agreement in evaluation of large vessel invasion was only slightly higher than would be seen by chance alone. This study highlights the need for criteria in evaluation of lymphovascular invasion, as this assessment may impact patient prognosis and thus change the course of clinical treatment

T145 Comprehensive flow cytometry tracking of regulatory T cells and other lymphocyte subsets during HD IL-2 therapy for melanoma

High dose IL-2 (HD IL-2) has been extensively used as an immunotherapy against metastatic melanoma However, why HD IL-2 is effective only in a subset of patients and whether predictive biomarkers, before or early during the course of therapy, can be used to improve response rates remain unresolved. In addition, it has been found that IL-2 therapy potently expands CD4+CD25+Foxp3+ T-regulatory cells (Tregs) but how Treg cell levels, phenotype, and function change and whether specific subsets of Tregs are activated and expanded during HD IL-2 therapy is remain unclear. In this study, we performed comprehensive multi-parameter FACS analysis of patient blood before and two days after the last bolus of IL-2 infusion during cycle 1 of HD IL-2 therapy. Two lymphocyte subsets were found to expand the most during the first cycle of IL-2 therapy: CD4+CD25+Foxp3+ Tregs expressing an activation marker, inducible costimulator (ICOS), and CD3-CD56hiCD16loPerforin+ NK cells. ICOS+ Tregs expressed significantly higher levels of CD25, Foxp3 and had a more activated phenotype than ICOS− Tregs as indicated by lower levels of CD45RA and CD127 expression. Further phenotypic characterization revealed a more suppressive phenotype on ICOS+ Treg with higher expression levels of CD39, CD73, and TGF-β/LAP than ICOS− Treg. ICOS+ Tregs were also the predominant Treg cells that secreted IL-10 and have potent T-cell suppressor function. Majority of ICOS+ Tregs from HD IL-2-treated patients were Ki67+ and exhibited an enhanced proliferative response to IL-2 ex vivo relative to ICOS− Tregs. Functional analysis revealed that ICOS+ Tregs secreted little IFN- and IL-2 in comparison to CD4+Foxp3 – cells. Furthermore, analysis on 38 IL-2-treated patients at MD Anderson, we found that non-responders had a significantly higher degree of ICOS+ Treg expansion than responders during the first cycle of IL-2 therapy, while no significant changes in the ICOS− or bulk Treg population. In conclusion, our data suggests that tracking changes in ICOS+ Tregs early during the course of HD IL-2 therapy may be a new predictive biomarker of clinical outcome

Recent Advances Concerning Certain Class of Geophysical Flows

This paper is devoted to reviewing several recent developments concerning certain class of geophysical models, including the primitive equations (PEs) of atmospheric and oceanic dynamics and a tropical atmosphere model. The PEs for large-scale oceanic and atmospheric dynamics are derived from the Navier-Stokes equations coupled to the heat convection by adopting the Boussinesq and hydrostatic approximations, while the tropical atmosphere model considered here is a nonlinear interaction system between the barotropic mode and the first baroclinic mode of the tropical atmosphere with moisture. We are mainly concerned with the global well-posedness of strong solutions to these systems, with full or partial viscosity, as well as certain singular perturbation small parameter limits related to these systems, including the small aspect ratio limit from the Navier-Stokes equations to the PEs, and a small relaxation-parameter in the tropical atmosphere model. These limits provide a rigorous justification to the hydrostatic balance in the PEs, and to the relaxation limit of the tropical atmosphere model, respectively. Some conditional uniqueness of weak solutions, and the global well-posedness of weak solutions with certain class of discontinuous initial data, to the PEs are also presented.Comment: arXiv admin note: text overlap with arXiv:1507.0523

Factors Associated with Sexual Violence against Men Who Have Sex with Men and Transgendered Individuals in Karnataka, India

There is a lack of information on sexual violence (SV) among men who have sex with men and transgendered individuals (MSM-T) in southern India. As SV has been associated with HIV vulnerability, this study examined health related behaviours and practices associated with SV among MSM-T.Data were from cross-sectional surveys from four districts in Karnataka, India.Multivariable logistic regression models were constructed to examine factors related to SV. Multivariable negative binomial regression models examined the association between physician visits and SV.A total of 543 MSM-T were included in the study. Prevalence of SV was 18% in the past year. HIV prevalence among those reporting SV was 20%, compared to 12% among those not reporting SV (p = .104). In multivariable models, and among sex workers, those reporting SV were more likely to report anal sex with 5+ casual sex partners in the past week (AOR: 4.1; 95%CI: 1.2-14.3, p = .029). Increased physician visits among those reporting SV was reported only for those involved in sex work (ARR: 1.7; 95%CI: 1.1-2.7, p = .012).These results demonstrate high levels of SV among MSM-T populations, highlighting the importance of integrating interventions to reduce violence as part of HIV prevention programs and health services

Abelian and nonabelian vector field effective actions from string field theory

The leading terms in the tree-level effective action for the massless fields of the bosonic open string are calculated by integrating out all massive fields in Witten's cubic string field theory. In both the abelian and nonabelian theories, field redefinitions make it possible to express the effective action in terms of the conventional field strength. The resulting actions reproduce the leading terms in the abelian and nonabelian Born-Infeld theories, and include (covariant) derivative corrections.Comment: 49 pages, 1 eps figur

Are ulcers a marker for invasive carcinoma in barrett's esophagus? data from a diagnostic variability study with clinical follow-up

We correlated follow-up information from 138 patients with Barrett's esophagus and varying degrees of dysplasia with the presence of ulcers. Methods A group of pathologist participants were asked to contribute patients’ initial biopsy slides showing Barrett's esophagus (BE) without dysplasia and with epithelial changes indefinite for dysplasia, low grade dysplasia (LGD), high grade dysplasia (HGD), and adenocarcinoma. From the initial 250 cases used for a diagnostic reproducibility study, follow-up information was available for 138 patients. Results There were 44 cases submitted as BE, 22 as BE with epithelial changes indefinite for dysplasia, 26 as BE with LGD, 33 as BE with HGD, and 13 as BE with adenocarcinoma. Ulcers were present in 35/138 cases (25%), including 3/44 cases of BE without dysplasia (7%), 2/22 cases of BE with epithelial changes indefinite for dysplasia (9%), 0/26 cases of BE with LGD (0%), 10/33 cases of BE with HGD (30%), and 7/13 cases of BE with adenocarcinoma (54%). On follow-up, there were no invasive carcinomas detected among the BE without dysplasia group (median follow-up = 38.5 months). Adenocarcinomas were detected in 4/22 cases (18%) submitted as BE with epithelial changes indefinite for dysplasia at 19, 55, 60, and 62 months and in 4/26 cases (15%) of BE with LGD at 9, 9, 11, and 60 months. None of these carcinomas occurred in cases in which an ulcer was present in the initial biopsy specimen. Among the 33 HGD cases, 20 (60%) were found to have adenocarcinoma on subsequent resection specimens. The presence of an ulcer with HGD increased the likelihood of finding carcinoma in the resection specimen, as 8/10 biopsies (80%) of HGD patients with ulcers had carcinoma, compared to 12/23 biopsies (52%) of HGD patients without ulcers. All of the cases interpreted as adenocarcinomas on biopsy were found either to have invasive carcinoma on esophageal resection or to have metastases that were demonstrated in unresectable patients. Conclusion If an ulcer accompanies HGD in a biopsy specimen from a patient with BE, it is likely that invasive carcinoma is also present at that time.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75186/1/j.1572-0241.2002.05420.x.pd

DNA damage alters DNA polymerase δ to a form that exhibits increased discrimination against modified template bases and mismatched primers

Human DNA polymerase δ (Pol δ4), a key enzyme in chromosomal replication, is a heterotetramer composed of the p125, p50, p68 and p12 subunits. Genotoxic agents such as UV and alkylating chemicals trigger a DNA damage response in which Pol δ4 is converted to a trimer (Pol δ3) by degradation of p12. We show that Pol δ3 has altered enzymatic properties: it is less able to perform translesion synthesis on templates containing base lesions (O6-MeG, 8-oxoG, an abasic site or a thymine-thymine dimer); a greater proofreading activity; an increased exonuclease/polymerase activity ratio; a decreased tendency for the insertion of wrong nucleotides, and for the extension of mismatched primers. Overall, our findings indicate that Pol δ3 exhibits an enhanced ability for the detection of errors in both primers and templates over its parent enzyme. These alterations in Pol δ3 show that p12 plays a major role in Pol δ4 catalytic functions, and provides significant insights into the rationale for the conversion of Pol δ4 to Pol δ3 in the cellular response to DNA damage

Strings between branes

D-brane configurations containing fundamental strings are constructed as classical solutions of Yang-Mills theory. The fundamental strings in these systems stretch between D-branes. In the case of D1-branes, this construction gives smooth (classical) resolutions of string junctions and string networks. Using a non-abelian Yang-Mills analysis of the string current, the string charge density is computed and is shown to have support in the region between the D-brane world-volumes. The 't Hooft-Polyakov monopole is analyzed using similar methods, and is shown to contain D-strings whose flux has support off the D-brane world-volume defined by the Higgs scalar field, when this field is interpreted in terms of a transverse dimension. The constructions presented here are used to give a qualitative picture of tachyon condensation in the Yang-Mills limit, where fundamental strings and lower-dimensional D-branes arise in a volume of space-time where brane-antibrane annihilation has occurred.Comment: 35 pages, 16 eps figures, JHEP style; v2: a comment adde