Uterine Papillary Serous Carcinoma and Endometrioid Carcinoma: Novel Immunostains with Respect to Clinical-Pathologic Factors

Background:Uterine papillary serous carcinoma (UPSC), also known as type II endometrial carcinoma, is an uncommon aggressive variant of endometrial carcinoma [1, 2]. Its tumorigenesis, as well as its clinical risk factors differ from the commonly occurring endometrioid carcinoma (EC) [3-5]. Typical pathologic factors also differ. Even with minimal myometrial invasion, lymph-vascular space invasion or tumor limited to polyps, UPSC has been found to be associated with widespread metastasis, recurrence, and poor survival [6]. Since UPSC may be difficult to differentiate from high grade endometrioid carcinoma, particularly in mixed carcinomas, immunohistochemical techniques may facilitate such diagnoses, and even potentially serve as prognostic factors. Three novel proteins, L523S (also known as KOC-K homology domain containing protein over expressed in cancer), an oncofetal RNA-binding protein; O8E (also known as CRxA-01), a novel protein involved in T-cell regulation; and WT1 (Wilm\u27s Tumor) a tumor suppressor gene, have shown positive expression in various cancers [7-13]. Their expression and prognostic implication in UPSC is unknown. Objectives: To evaluate L523S, O8E and WT1 expression in UPSC and EC. To correlate clinical-pathologic factors to these staining patterns. Methods: A search of the University of Massachusetts Medical Center database was performed for UPSC from 1998 to 2003, and for EC from 2002-03. The UPSC group consisted of 31 patients, and EC group of 63 patients. All cases were reviewed by the authors EK and BX. A tissue block containing the best representation of UPSC and EC was selected for each case, and stained for L523S, O8E, and WT1, on a Dako autostainer, per protocol [13]. Histologic scoring of all stains were conducted by one examiner, EK. A retrospective chart review of each patient was performed to extract clinical and pathologic variables. Staining outcomes were tested using a Fisher\u27s Exact test, with significance level determined at α=0.05. Demographic variables of normal distribution were tested using a heteroscedastic T-test (2-tail, α=0.05). Results: Significant differences were found for age (p=0.004) and BMI (p=0.016) between UPSC and EC. Racial distribution, gravidity, and parity were similar. EC patients had greater use of hormone replacement therapy, oral contraceptives, and cigarette smoking. They also had greater occurrence of diabetes (38.33% vs 17.34%) and family history of breast cancer (33.93% vs 23.08%) and gynecologic cancers (30.36% vs 19.23%), although UPSC patients had a greater occurrence of personal history of breast cancer (21.42% vs 14.75%). Overall, UPSC had a greater distribution of higher-staged cases. The stage distribution of UPSC and EC were as follows: Stage I UPSC (10/26, 38.46%) and EC (48/63, 76.19%); Stage II UPSC (3/26, 11.54%) and EC (5/63, 7.94%); Stage III (10/26, 38.46%) and EC (10/63, 15.87%); Stage IV UPSC (3/26, 11.54%) and EC (0/64, 0%). UPSC patients had higher rates of recurrence (50% vs 7.01%). Significantly more UPSC stained positive for L523S (p\u3c0.0001) and WT1 (p=0.0015). There is a slight trend of higher surgical stage for UPSC L523S(+) cases versus UPSC L523S(-) cases: L523S(+) Stage I and II consisted of 7/17 (41.18%) cases, and L523S(-) of 5/8 (62.50%) cases. L523S(+) Stage III and IV consisted of 10/17 (58.82%) cases, and L523S(-) of 3/8 (37.5%) cases. Of the UPSC L523S(+) cases, 3 patients have expired, 2 of whom were staged as IIB and IIIA. Of the serous L523(-) cases, 2 patients have expired, staged at IIIA and IIIC. Of the endometrioid L523(+) cases, 2 were stage IA and one was of stage IB. For WT1, UPSC showed five positive cases, whereas no EC cases were positive. Of the UPSC WT1(+) cases, all were stage III, and three patients have expired. In contrast, staining for O8E did not significantly differ between UPSC and EC (p=0.1851). Discussion UPSC is an uncommon, aggressive variant of endometrial carcinoma. Similar to previous studies, UPSC is found in patients of greater age, and BMI, and less associated with diabetes, and hormone use. The higher rate of family history of breast and gynecological cancer in the EC group may reflect the hormone-positive nature of most EC tumors. However, it is unclear why UPSC patients had a greater percentage of breast cancer. The higher rate of expired UPSC patients may reflect the aggressive nature of the disease, or in this study, a longer duration of follow-up. The staining pattern most significantly differed between the serous and endometrioid groups with L523, suggesting that it may be a tool to aid pathologist?s diagnosis of UPSC, particularly in mixed cases. Additionally, L523 may be a marker for worse prognosis in UPSC cases. However, the study was limited by the small number of UPSC cases. WT1 also significantly stained more serous cases compared to endometrioid cases. However, the absolute number of serous WT1(+) was quite small. It is unclear if these cases consisted solely of UPSC with metastasis to the adnexa, or if these cases were actually dual ovarian and endometrial primaries, or potentially even ovarian carcinomas that had metastasized to the uterus. O8E staining did not significantly differ between UPSC and EC, and thus would not aid in the histologic differentiation between the two. Inherent limitations in this study included loss-to-followup, incomplete charts, follow-up with providers outside of this hospital, lack of abundant tissue and loss of tissue blocks. Further study would include increasing the number of UPSC cases, as well as including EC cases diagnosed during the same time frame as UPSC cases. Conclusions: UPSC significantly expresses L523S in comparison to EC. Positive staining of UPSC cases may be associated with higher stage and worse prognosis. Further investigation of additional UPSC cases may clarify the utility of this novel immuno-marker. 1. Hendrickson, M., et al., Uterine papillary serous carcinoma: a highly malignant form of endometrial adenocarcinoma. Am J Surg Pathol, 1982. 6(2): p. 93-108. 2. Bokhman, J.V., Two pathogenetic types of endometrial carcinoma. Gynecol Oncol, 1983. 15(1): p. 10-7. 3. Ambros, R.A., et al., Endometrial intraepithelial carcinoma: a distinctive lesion specifically associated with tumors displaying serous differentiation. Hum Pathol, 1995. 26(11): p. 1260-7. 4. Carcangiu, M.L. and J.T. Chambers, Uterine papillary serous carcinoma: a study on 108 cases with emphasis on the prognostic significance of associated endometrioid carcinoma, absence of invasion, and concomitant ovarian carcinoma. Gynecol Oncol, 1992. 47(3): p. 298-305. 5. Slomovitz, B.M., et al., Uterine papillary serous carcinoma (UPSC): a single institution review of 129 cases. Gynecol Oncol, 2003. 91(3): p. 463-9. 6. Sherman, M.E., et al., Uterine serous carcinoma. A morphologically diverse neoplasm with unifying clinicopathologic features. Am J Surg Pathol, 1992. 16(6): p. 600-10. 7. Dupont, J., et al., Wilms Tumor Gene (WT1) and p53 expression in endometrial carcinomas: a study of 130 cases using a tissue microarray. Gynecol Oncol, 2004. 94(2): p. 449-55. 8. Egan, J.A., et al., Differential expression of WT1 and p53 in serous and endometrioid carcinomas of the endometrium. Int J Gynecol Pathol, 2004. 23(2): p. 119-22. 9. Goldstein, N.S. and A. Uzieblo, WT1 immunoreactivity in uterine papillary serous carcinomas is different from ovarian serous carcinomas. Am J Clin Pathol, 2002. 117(4): p. 541-5. 10. Ciampa, A., et al., CRxA-01 and L523 expression in serous neoplasms of the ovary: potential role in differentiating serous tumors of low malignant potential from serous carcinomas. Mod Pathol, 2003. 17: p. 194A. 11. Ciampa, A., et al., Mammaglobin and CRxA-01 in pleural effusion cytology: potential utility of distinguishing metastatic breast carcinomas from other cytokeratin 7-positive/cytokeratin 20-negative carcinomas. Cancer, 2004. 102(6): p. 368-72. 12. Wang, T., et al., L523S, an RNA-binding protein as a potential therapeutic target for lung cancer. Br J Cancer, 2003. 88(6): p. 887-94. 13. Yantiss, R.K., et al., KOC (K homology domain containing protein overexpressed in cancer): a novel molecular marker that distinguishes between benign and malignant lesions of the pancreas. Am J Surg Pathol, 2005. 29(2): p. 188-95

Henry George’s Contribution to Socialism in America, 1870-1900

The Gilded Age was a period of industrial development in the United States from approximately 1870 to 1900. In many ways, it helped to usher in the modern world. With the large growth in business, there also arose a displacement among workers who were migrating from farms to cities and adapting to new methods of management and business. This dissatisfaction led to the creation of labor unions and the spread of socialism in America. Henry George (1839 to 1897), a political and social leader of this period, was inspired to write his manifesto, Progress and Poverty: An Inquiry into the Cause of Industrial Depressions, and of Increase of Want with Increase of Wealth: The Remedy, by the social conditions he witnessed. Many socialist thinkers during the Gilded Age and since read George’s work and were struck by its socialist leanings. In their writings, most of them conceded that George contributed to bringing socialist ideas to the public with his bestseller. However, some thinkers took issue with his single land tax principle that they judged to be overrated or not radical enough. George has been largely overlooked in the history of the Gilded Age, but during George’s life, Progress and Poverty reached the minds of reformers, politicians, writers, lecturers, and social leaders.Histor

A conserved acidic patch in the Myb domain is required for activation of an endogenous target gene and for chromatin binding

The c-Myb protein is a transcriptional regulator initially identified by homology to the v-Myb oncoprotein, and has since been implicated in human cancer. The most highly conserved portion of the c-Myb protein is the DNA-binding domain which consists of three imperfect repeats. Many other proteins contain one or more Myb-related domains, including a number of proteins that do not bind directly to DNA. We performed a phylogenetic analysis of diverse classes of Myb-related domains and discovered a highly conserved patch of acidic residues common to all Myb-related domains. These acidic residues are positioned in the first of three alpha-helices within each of the three repeats that comprise the c-Myb DNA-binding domain. Interestingly, these conserved acidic residues are present on a surface of the protein which is distinct from that which binds to DNA. Alanine mutagenesis revealed that the acidic patch of the third c-Myb repeat is essential for transcriptional activity, but neither for nuclear localization nor DNA-binding. Instead, these acidic residues are required for efficient chromatin binding and interaction with the histone H4 N-terminal tail

Deletion of astroglial CXCL10 delays clinical onset but does not affect progressive axon loss in a murine autoimmune multiple sclerosis model.

Multiple sclerosis (MS) is characterized by central nervous system (CNS) inflammation, demyelination, and axonal degeneration. CXCL10 (IP-10), a chemokine for CXCR3+ T cells, is known to regulate T cell differentiation and migration in the periphery, but effects of CXCL10 produced endogenously in the CNS on immune cell trafficking are unknown. We created floxed cxcl10 mice and crossed them with mice carrying an astrocyte-specific Cre transgene (mGFAPcre) to ablate astroglial CXCL10 synthesis. These mice, and littermate controls, were immunized with myelin oligodendrocyte glycoprotein peptide 35-55 (MOG peptide) to induce experimental autoimmune encephalomyelitis (EAE). In comparison to the control mice, spinal cord CXCL10 mRNA and protein were sharply diminished in the mGFAPcre/CXCL10fl/fl EAE mice, confirming that astroglia are chiefly responsible for EAE-induced CNS CXCL10 synthesis. Astroglial CXCL10 deletion did not significantly alter the overall composition of CD4+ lymphocytes and CD11b+ cells in the acutely inflamed CNS, but did diminish accumulation of CD4+ lymphocytes in the spinal cord perivascular spaces. Furthermore, IBA1+ microglia/macrophage accumulation within the lesions was not affected by CXCL10 deletion. Clinical deficits were milder and acute demyelination was substantially reduced in the astroglial CXCL10-deleted EAE mice, but long-term axon loss was equally severe in the two groups. We concluded that astroglial CXCL10 enhances spinal cord perivascular CD4+ lymphocyte accumulation and acute spinal cord demyelination in MOG peptide EAE, but does not play an important role in progressive axon loss in this MS model

Robust Analysis of Metabolic Pathways

Flux Balance Analysis (FBA) is a widely used computational model for studying the metabolic pathways of cells and the role individual metabolites and reactions play in maintaining cell function. However, the successes of FBA have been limited by faulty biological assumptions and computational imperfections. We introduce Robust Analysis of Metabolic Pathways (RAMP) to provide a more theoretically sound and computationally accurate model of cellular metabolism. RAMP overcomes the faulty assumptions of traditional FBA by allowing deviation from steady-state and accounting for variability across a cellular culture. Computationally, RAMP more successfully predicts the lethality of gene knockouts and reduces degeneracy in optimal ux values. Analytical results establish the stability of RAMP under perturbations in modeling parameters. The inclusion of new modeling parameters in RAMP opens the possibility of modeling different cellular cultures in a wider range of conditions, including non- optimized cultures. We conclude that RAMP is an improvement over traditional FBA and deserves further study

HPV Reflex Testing in Menopausal Women

Objective. To determine the frequency of high risk (HR) HPV and intraepithelial neoplasia following ASCUS pap cytology screens in menopausal women. Study Design. Following IRB approval, we performed a retrospective review of all cases of ASCUS pap tests, HPV results, and relevant clinical-pathologic data in women age 50 or over from November 2005 to January 2007 within a tertiary care center. Statistical analyses were performed in EXCEL. Results. 344 patients were analyzed for a total of 367 screening pap tests. 25.29% (87/344) patients were HR HPV positive, with greater percentages of HR HPV cases occurring in women age 65–74. Within HR HPV cases, 79.3% (69/87) underwent colposcopy. 27.5% (19/69) biopsy proven lesions were discovered, including cervical, vulvar or vaginal (intraepithelial neoplasia). Within the negative HR HPV group 3.1% (8/257) patients were diagnosed with dysplasia or carcinoma. Within both HR HPV positive and negative groups, patients with no prior history of lower genital tract lesions or cancer were identified. Conclusion. Reflex HPV testing plays an important role in ASCUS triage in menopausal women. Pap test screening and HPV testing should not be limited to women of reproductive age as they may aid in the diagnosis of intraepithelial neoplasia in women of older age

Immune Dysfunction and Autoimmunity as Pathological Mechanisms in Autism Spectrum Disorders

Autism spectrum disorders (ASD) are a group of heterogeneous neurological disorders that are highly variable and are clinically characterized by deficits in social interactions, communication, and stereotypical behaviors. Prevalence has risen from 1 in 10,000 in 1972 to 1 in 59 children in the United States in 2014. This rise in prevalence could be due in part to better diagnoses and awareness, however, these together cannot solely account for such a significant rise. While causative connections have not been proven in the majority of cases, many current studies focus on the combined effects of genetics and environment. Strikingly, a distinct picture of immune dysfunction has emerged and been supported by many independent studies over the past decade. Many players in the immune-ASD puzzle may be mechanistically contributing to pathogenesis of these disorders, including skewed cytokine responses, differences in total numbers and frequencies of immune cells and their subsets, neuroinflammation, and adaptive and innate immune dysfunction, as well as altered levels of immunoglobulin and the presence of autoantibodies which have been found in a substantial number of individuals with ASD. This review summarizes the latest research linking ASD, autoimmunity and immune dysfunction, and discusses evidence of a potential autoimmune component of ASD