Lymphomas of the Breast: Primary and Secondary Involvement

Cancer. Jan, 2002  |  Pubmed ID: 11815954

The involvement of the breast by lymphoma is a rare form of extralymph node lymphoma and represents either primary disease or systemic involvement. The authors hypothesized that screening mammography may influence the detection of lymphomatous involvement of the breast.

Atypical Glandular Cells of Undetermined Significance in Conventional Cervical/vaginal Smears and Thin-layer Preparations

Cancer. Feb, 2002  |  Pubmed ID: 11836696

Biopsy follow-up of a cervical/vaginal smear interpretation of atypical glandular cells of undetermined significance (AGUS) most often reveals either a benign reactive process or a squamous cervical intraepithelial neoplasia (CIN) rather than a glandular one. The ThinPrep Papanicolaou test (TP) has been shown to increase diagnostic sensitivity for CIN. To the authors' knowledge there are few studies examining its effectiveness in diagnosing uterine glandular lesions, either endocervical or endometrial. The authors compared outcomes after AGUS interpreted in TP specimens and conventional smear preparations (CPs).

Bimaxillary Chondrosarcoma: Clinical, Radiologic, and Histologic Correlation

AJNR. American Journal of Neuroradiology. Apr, 2002  |  Pubmed ID: 11950664

In this report, we describe an unusual case of chondrosarcoma that involved the entire bimaxillary and nasal skeleton. The pathogenesis, correlation of histopathology with radiology, and management of chondrosarcoma are reviewed.

The Value of Wilms Tumor Susceptibility Gene 1 in Cytologic Preparations As a Marker for Malignant Mesothelioma

Cancer. Apr, 2002  |  Pubmed ID: 11954027

It has been shown that detection of the Wilms tumor susceptibility gene 1 protein (WT1) has diagnostic utility in the distinction of mesothelioma from adenocarcinoma in tissue sections of pleural tumors. This immunohistochemical study evaluates the effectiveness of WT1 as a marker for malignant mesothelioma in paraffin sections of cell block preparations derived from effusion specimens.

WT1, Estrogen Receptor, and Progesterone Receptor As Markers for Breast or Ovarian Primary Sites in Metastatic Adenocarcinoma to Body Fluids

American Journal of Clinical Pathology. May, 2002  |  Pubmed ID: 12090423

In tissue sections, detection of the Wilms tumor susceptibility gene 1 (WTI) protein, the hormonal receptors for estrogen (ER) and progesterone (PR), and gross cystic disease fluid protein (GCDFP) are useful for diagnosing ovarian and breast adenocarcinomas. We evaluated these markers for cytology cell-block preparations from 96 effusion specimens (metastases from 29 breast, 22 ovarian, and 45 adenocarcinomas from other sites). WTI protein was reactive in 19 cases inetastatic from ovary (86%), 2 from breast (7%), and none from other sites (specificity; 97%). Of the metastatic breast carcinomas, 21(72%) were reactive for ER, 15(52%) for PR, and 13 (45%) for both (combined specificity, 84%). GCDEP was reactive in only 4 breast cancer cases (14%). Ovarian tumors also were frequently positive for ER (19 [86%]), PR (II [SO%]), or both (10 [45%]). WTI protein is an effective marker for ovarian adenocarcinoma, especially in ascites. The detection of ER and PR in metastatic adenocarcinoma from pleural or pericardial efflusions can distinguish breast from lung primary sites. Reactivity for ER and PR did not distinguish between breast and ovarian metastases; however; studies for WTI protein and GCDFP may aid in making this distinction.

Fine-needle Aspiration Cytology of Lymphoproliferative Disorders in the Immunosuppressed Patient: the Diagnostic Utility of in Situ Hybridization for Epstein-Barr Virus

Diagnostic Cytopathology. Jun, 2002  |  Pubmed ID: 12112825

We examined the diagnostic utility of fine-needle aspiration (FNA) in the immunosuppressed patient with particular attention to the value of in situ hybridization for Epstein-Barr virus encoded RNA (EBER), a test frequently performed on tissue sections in this setting. Six patients with adenopathy were identified: three with prior solid organ transplantation, two with prior bone marrow transplantation, and one with human immunodeficiency virus. Cytologic findings in involved tissues were positive for non-Hodgkin's lymphoma in one case, suspicious or atypical in three cases, negative/reactive in one case, and nondiagnostic in one case due to insufficient material. Two aspirates had a polymorphous lymphoid appearance; three showed predominantly monomorphous lymphoid morphology. Retrospectively, 4/4 FNA cell blocks were positive for EBER in a large proportion of atypical lymphoid cells. Together with the cytologic findings, EBER detection allows for more specific classification of these FNA samples as EBV-associated lymphoid proliferations.

Pancreatic Fine Needle Aspiration. A Comparison of Computed Tomographic and Endoscopic Ultrasonographic Guidance

Acta Cytologica. Sep-Oct, 2003  |  Pubmed ID: 14526668

To compare the sensitivity and specificity of pancreatic fine needle aspiration (FNA) with computed tomography (CT) and endoscopic ultrasound (EUS) guidance.

T-bet Regulates Metastasis Rate in a Murine Model of Primary Prostate Cancer

Cancer Research. Jan, 2004  |  Pubmed ID: 14744755

The local progression of primary tumors is extrinsically controlled by type 1 immune responses, particularly via the cytokine IFN-gamma, whose secretion is highly dependent on helper T cells. The T-box transcription factor T-bet (Tbx21) plays a critical role in the development of type 1 helper T cells and is essential for the production of IFN-gamma. Here, the T-bet pathway in the autochthonous transgenic adenocarcinoma mouse prostate model is demonstrated to have only a modest effect on the characteristics of primary prostate cancers but rather exerts a significant suppressor function in the development of metastatic disease.

Neonatal Respiratory Distress Syndrome As a Function of Gestational Age and an Assay for Surfactant-to-albumin Ratio

Obstetrics and Gynecology. Mar, 2004  |  Pubmed ID: 14990407

Neonatal respiratory distress syndrome (RDS) affects approximately 1% of live births, and the probability of RDS continues to be a major determinant in the timing of delivery. This study was designed to investigate the optimal gestational age-specific cutoff value for a surfactant-to-albumin ratio assay for predicting RDS.

Vulvar Acanthosis with Altered Differentiation: a Precursor to Verrucous Carcinoma?

The American Journal of Surgical Pathology. May, 2004  |  Pubmed ID: 15105653

Verrucous carcinoma (VC) of the vulva is a rare variant of squamous cell carcinoma (SCC) of the vulva that afflicts older women and is characterized by a well-differentiated morphology with minimal nuclear atypia. The pathogenesis of VC is uncertain and a putative role for human papillomavirus (HPV) is doubtful. We analyzed 9 vulvar VCs from 7 patients diagnosed as VC of the vulva over the past 10 years at Brigham and Women's Hospital and Beth Israel Deaconess Medical Center. The patients ranged from 75 to 93 years in age (median, 83 years). One also involved the vagina and another coexisted with a keratinizing SCC. VC was associated with lichen sclerosus in 1 case; 7 others contained lichen simplex chronicus with verrucous architecture. In 7 cases, a distinctive noninvasive squamous epithelial proliferation, exhibiting a triad of marked acanthosis with variable verruciform architecture, loss of the granular cell layer with superficial epithelial cell pallor, and multilayered parakeratosis. We have designated these changes vulvar acanthosis with altered differentiation. In 5 of the 9 lesions, formalin-fixed, paraffin-embedded material was available for polymerase chain reaction analysis of HPV nucleic acids and all scored HPV negative. In conclusion, VC is a rare HPV-negative neoplasm that may be associated with other HPV-negative SCCs or its precursors, shares similar morphologic risk factors (lichen sclerosus and lichen simplex chronicus), and is frequently associated with an unusual intraepithelial lesion that can be distinguished from both classic and differentiated forms of vulvar intraepithelial neoplasia. The possibility that vulvar acanthosis with altered differentiation is a precursor to, or a risk factor for, vulvar carcinoma, merits further study.

Enhanced Detection of Atypical Hyperplasia in Endometrial Polyps by PTEN Expression

Applied Immunohistochemistry & Molecular Morphology : AIMM / Official Publication of the Society for Applied Immunohistochemistry. Mar, 2004  |  Pubmed ID: 15163017

Endometrial hyperplasia is difficult to recognize within endometrial polyps because of the background of randomly distributed irregular glands. The loss of expression of the PTEN oncogene is characteristic of endometrial cancers and clinically significant hyperplasia. Using immunohistochemical staining for the PTEN protein, we studied 12 endometrial polyps that were noted to contain foci of complex hyperplasia or glandular crowding. Loss of PTEN staining was found in 3 cases, suggesting a precancerous lesion. Moreover, 2 of these cases were originally classified as complex hyperplasia without atypia and 1 as merely glandular crowding. Thus, in selected cases, the loss of PTEN expression in an area of glandular crowding can highlight biologically significant lesions and afford a more definitive diagnosis.

Long-term Follow-up After Polypectomy Treatment for Adenoma-like Dysplastic Lesions in Ulcerative Colitis

Clinical Gastroenterology and Hepatology : the Official Clinical Practice Journal of the American Gastroenterological Association. Jul, 2004  |  Pubmed ID: 15224277

A previously published study by our group suggested that adenoma-like dysplasia-associated lesions or masses (DALMs) in ulcerative colitis (UC) may be treated adequately by polypectomy and continued endoscopic surveillance. The length of follow-up evaluation in these patients averaged only 42 months. The purpose of this study was to evaluate the long-term outcome of our previously defined group of UC patients, all with adenoma-like DALMs, who were treated by polypectomy.

Expression of Candidate Tumor Markers in Ovarian Carcinoma and Benign Ovary: Evidence for a Link Between Epithelial Phenotype and Neoplasia

Human Pathology. Aug, 2004  |  Pubmed ID: 15297969

EpCAM, epithelial membrane antigen (EMA)-mucin 1 (MUC1), mesothelin, and CD9 have been reported to be overexpressed at the RNA level in ovarian carcinomas. By using immunohistochemistry, we profiled the protein expression of these gene products in ovarian carcinoma tissues and compared them with benign ovarian surface epithelium (OSE) and cortical inclusion cysts (CICs). Immunoreactivity for EMA and calretinin were used to define epithelial and mesothelial differentiation in nontumor tissues, respectively. Papillary serous (n = 16) and endometrioid (n = 10) tumors were immunopositive for EMA/MUC1 (100%), mesothelin (75% and 30%, respectively), CD9 (88% and 90%, respectively), and EpCAM (100%). All ovarian carcinomas and carcinoma cell lines tested were negative for calretinin. In nonneoplastic ovary, both OSE and CICs ranged from flat-to-cuboidal to stratified and ciliated in appearance. OSE with a cuboidal morphology had a similar immunoreactivity as omental peritoneum, expressing calretinin, mesothelin, and CD9. In contrast, CICs with stratified and ciliated epithelium show expression patterns similar to those in fallopian tubes. They frequently expressed EMA, EpCAM, mesothelin, and CD9. This immunophenotype is preserved in ovarian carcinomas, suggesting that Müllerian metaplasia signals the acquisition of these markers and that their expression is maintained in ovarian carcinomas that originate from this epithelium.

A Mesothelial Cyst of the Round Ligament Presenting As an Inguinal Hernia After Gonadotropin Stimulation for in Vitro Fertilization

Fertility and Sterility. Oct, 2004  |  Pubmed ID: 15482776

To report the case of a round ligament cyst which, as the result of gonadotropin stimulation for IVF, simulated an incarcerated inguinal hernia.

Microglandular Hyperplasia: a Model for the De Novo Emergence and Evolution of Endocervical Reserve Cells

Human Pathology. Feb, 2005  |  Pubmed ID: 15754292

Microglandular hyperplasia (MGH) of the cervix in human beings is associated early with gland proliferation and terminates in mature squamous metaplasia. Using antibodies to basal cell markers, we analyzed biopsies with MGH to profile the distribution and evolution of reserve cells and their relationship to these epithelial components.

Prediction of Endometrial Carcinoma by Subjective Endometrial Intraepithelial Neoplasia Diagnosis

Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc. Mar, 2005  |  Pubmed ID: 15529181

Endometrial intraepithelial neoplasia (also known as 'EIN') is a precursor to endometrioid endometrial adenocarcinoma characterized by monoclonal growth of mutated cells, a distinctive histopathologic appearance, and 45-fold elevated cancer risk. We have applied diagnostic criteria for EIN to 97 successive endometrial biopsies classified as hyperplastic according to World Health Organization criteria and correlated results with computer-assisted morphometry (D-score) and clinical cancer outcomes. Three pathologists separately reviewed all cases for presence or absence of EIN using published criteria (gland area>stromal area, cytologic change in focus of altered architecture, lesion size>1 mm, and exclusion of cancer and mimics). Discordant cases were resolved by a consensus review at a multiheaded scope. Clinical outcomes were obtained in 84 patients from patient visit and pathology records. Diagnoses of presence or absence of EIN were unanimous among all three pathologists in 75% of cases, and intraobserver-reproducibility was very good (kappa 0.73-0.90). Cases rediagnosed as EIN encompassed hyperplasias previously diagnosed as atypical (n=18) or nonatypical (eight complex, two simple). Eight follow-up cancers were scattered between hyperplasia types (5/21 atypical, 3/63 nonatypical), but all classified as EIN (8/25) and D-score

Human Epididymis Protein 4 (HE4) is a Secreted Glycoprotein That is Overexpressed by Serous and Endometrioid Ovarian Carcinomas

Cancer Research. Mar, 2005  |  Pubmed ID: 15781627

Among the genes most commonly identified in gene expression profiles of epithelial ovarian carcinomas (EOC) is the gene for human epididymis protein 4 (HE4). To ascertain its clinical utility, we did a comprehensive assessment of HE4 protein expression in benign and malignant ovarian and nonovarian tissues by immunohistochemistry. In comparison with normal surface epithelium, which does not express HE4, we found that cortical inclusion cysts lined by metaplastic Mullerian epithelium abundantly express the protein. Its expression in tumors was restricted to certain histologic subtype: 93% of serous and 100% of endometrioid EOCs expressed HE4, whereas only 50% and 0% of clear cell carcinomas and mucinous tumors, respectively, were positive. Tissue microarrays revealed that the majority of nonovarian carcinomas do not express HE4, consistent with our observation that HE4 protein expression is highly restricted in normal tissue to the reproductive tracts and respiratory epithelium. HE4 is predicted to encode a secreted protein. Using reverse transcription-PCR, we identified ovarian cancer cell lines that endogenously overexpress HE4. Cultured medium from these cells revealed a secreted form of HE4 that is N-glycosylated. This observation is consistent with the recent report that HE4 circulates in the bloodstream of patients with EOC. Therefore, HE4 is a secreted glycoprotein that is overexpressed by serous and endometrioid EOCs. Its expression in cortical inclusion cysts suggests that formation of Mullerian epithelium is a prerequisite step in the development of some types of EOCs.

Readers' Responses to the Webcast Video Editorial Entitled "resuscitating the Autopsy"

MedGenMed : Medscape General Medicine. 2005  |  Pubmed ID: 16385709

Neocortical Neuronal Arrangement in Miller Dieker Syndrome

Acta Neuropathologica. May, 2006  |  Pubmed ID: 16456669

Miller Dieker syndrome (MDS, type I lissencephaly) is a neuronal migration disorder, which is caused by deletions along the short arm of chromosome 17 (17p13.3). Recent studies would suggest that the cortical lamination in MDS is inverted, based on morphological criteria. The present neuropathological study examines the cerebral cortex from a 33-week old fetus with MDS using both neuronal and laminar-specific markers. These expression studies demonstrate a relatively preserved cortex and cortical lamination, overlying a layer of immature neurons in MDS brain. The findings are consistent with both a migratory and proliferative defect, giving rise to lissencephaly. Moreover, characterization of such rare human malformations of cortical development by immunohistochemical techniques will provide a greater understanding of the underlying mechanisms.

Intake of Folate and Related Nutrients in Relation to Risk of Epithelial Ovarian Cancer

American Journal of Epidemiology. Jun, 2006  |  Pubmed ID: 16554344

Assessments of the relation between folate intake and ovarian cancer risk have been limited and inconsistent. Therefore, the authors prospectively examined the association of dietary and supplemental intakes of folate, methionine, and vitamin B(6) with ovarian cancer risk among 80,254 Nurses' Health Study participants. Beginning in 1976, women completed biennial questionnaires assessing ovarian cancer risk factors; starting in 1980, food frequency questionnaires were administered every 2-4 years. During 22 years of follow-up (1980-2002), the authors confirmed 481 incident epithelial ovarian cancers. There were no associations between total folate (top quintile vs. bottom: relative risk (RR) = 1.21, 95% confidence interval (CI): 0.92, 1.60), methionine (RR = 1.00, 95% CI: 0.76, 1.33), dietary vitamin B(6) (RR = 1.09, 95% CI: 0.81, 1.47), or total vitamin B(6) (RR = 1.13, 95% CI: 0.85, 1.51) intake and ovarian cancer risk. Higher dietary folate was associated with a modestly decreased risk after exclusion of cases diagnosed during the 4 follow-up years after dietary assessment (RR = 0.66, 95% CI: 0.43, 1.03) and for the serous subtype (RR = 0.51, 95% CI: 0.31, 0.84). Results did not vary by alcohol intake, multivitamin use, menopausal status, or oral contraceptive use. There was little evidence that folate, methionine, and vitamin B(6) are important in ovarian cancer risk, although dietary folate was inversely associated with risk in some analyses.

Impaired Proliferation and Migration in Human Miller-Dieker Neural Precursors

Annals of Neurology. Jul, 2006  |  Pubmed ID: 16642511

Miller-Dieker syndrome (MDS) is a malformation of cortical development that results in lissencephaly (meaning smooth brain). This disorder is caused by heterozygous deletions on chromosome 17p13.3, including the lissencephaly 1 (LIS1) gene. Various mouse models have been used as an experimental paradigm in understanding human lissencephaly, but clear limitations exist in these studies, particularly because mice are naturally lissencephalic. Thus, the objective of this article was to establish human neural precursor cell lines from postmortem MDS tissue and to characterize the pathological cellular processes that contribute to the human lissencephalic phenotype.

Molecular and Pathologic Aspects of Endometrial Carcinogenesis

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. Oct, 2006  |  Pubmed ID: 17028294

Endometrial cancer is the most common gynecological malignancy, with 41,000 new cases projected in the United States for 2006. Two different clinicopathologic subtypes are recognized: the estrogen-related (type I, endometrioid) and the non-estrogen-related types (type II, nonendometrioid such as papillary serous and clear cell). The morphologic differences in these cancers are mirrored in their molecular genetic profile with type I showing defects in DNA-mismatch repair and mutations in PTEN, K-ras, and beta-catenin, and type II showing aneuploidy and p53 mutations. This article reviews the genetic aspects of endometrial carcinogenesis and progression. We will define the precursor lesion of type I endometrioid cancer and the role of genetics and estrogen in its progression.

Does Physiologic Breakdown Mask Significant Pathology in Endometrial Biopsies? A Retrospective Case-control Study

Archives of Pathology & Laboratory Medicine. Dec, 2006  |  Pubmed ID: 17149962

Adequacy criteria for endometrial biopsy samples do not exist.

Monoclonal Antibody MOC-31 Reactivity As a Marker for Adenocarcinoma in Cytologic Preparations

Cancer. Feb, 2006  |  Pubmed ID: 16329115

It has been shown previously that detection of the epithelial membrane antigen using the mouse monoclonal antibody MOC-31 has diagnostic utility in the distinction between mesothelioma and metastatic carcinoma in body fluids. The current immunohistochemical study confirmed the effectiveness of MOC-31 as a marker for adenocarcinoma from a broad range of primary sites in body fluid cytology prepared as paraffin sections of cell blocks.

Diagnosis of Chronic Endometritis in Biopsies with Stromal Breakdown

Human Pathology. Apr, 2007  |  Pubmed ID: 17188330

Plasma cells are the hallmark of chronic endometritis but are not specific for upper tract infection. Plasma cells have also been noted in hormonally mediated endometrial disorders in association with gland architectural changes ("disordered proliferative" and "anovulatory" patterns), and stromal breakdown. We reviewed benign endometrial biopsies diagnosed at Beth Israel Deaconess Medical Center over a 2-year period described as disordered/anovulatory patterns +/- stromal breakdown. Cases were excluded if tissue was not available; women were younger than 50 years where most diagnoses were atrophic or cancer; or diagnoses were secretory, menstrual endometrium, or polyps. The remaining 61 cases were compared to 33 samples of unremarkable proliferative endometrium. Plasma cells were quantified on hematoxylin and eosin-stained sections and using a histochemical stain methyl green pyronin. The indication for biopsy was an abnormal pattern of bleeding in 34 cases, infertility workup in 7, incidental part of workup for pain, or other findings in 5. The majority of disordered proliferative endometrium had plasma cells (61% grade 1, 17% grade 2) all seen on methyl green pyronin staining only. Two thirds of proliferative endometrium with breakdown showed plasma cells (19% grade 1, 39% grade 2, 10 % grade 3). Plasma cells were rare in inactive endometrium and noted in only 18% of unremarkable proliferative endometrium, all grade 1. Plasma cells are commonly present in the endometrium of women with dysfunctional uterine bleeding and focal stromal breakdown. Given the lack of clinical evidence for infection, the inflammation likely represents a physiologic process.

JC Virus Granule Cell Neuronopathy in a Child with CD40 Ligand Deficiency

Pediatric Neurology. Mar, 2007  |  Pubmed ID: 17352955

JC virus infection of the brain typically causes progressive multifocal leukoencephalopathy, a demyelinating disease that rarely involves gray matter. This report presents a case of cerebellar degeneration associated with JC virus infection in a male with CD40 ligand deficiency resulting in hyperimmunoglobulin M type 1. This patient exhibited a progressive cerebellar ataxia with progressive atrophy of the cerebellar cortex in association with the presence of JC virus in the spinal fluid. JC virus infection should be considered in the differential diagnosis of ataxia in children with inherited immunodeficiencies.

Breastfeeding and Risk of Ovarian Cancer in Two Prospective Cohorts

Cancer Causes & Control : CCC. Jun, 2007  |  Pubmed ID: 17450440

To describe the association between breastfeeding and ovarian cancer risk in two prospective cohorts.

A Prospective Study of Dietary Flavonoid Intake and Incidence of Epithelial Ovarian Cancer

International Journal of Cancer. Journal International Du Cancer. Nov, 2007  |  Pubmed ID: 17471564

Flavonoids are antioxidant compounds found in plants, including fruits, vegetables and tea. No prior prospective studies have examined the association between intake of flavonoids in the flavonol and flavone subclasses and ovarian cancer risk. We analyzed the association between intake of 5 common dietary flavonoids and incidence of epithelial ovarian cancer among 66,940 women in the Nurses' Health Study. We calculated each participant's intake of myricetin, kaempferol, quercetin, luteolin and apigenin from dietary data collected at multiple time points, and used Cox proportional hazards regression to model the incidence rate ratio (RR) of ovarian cancer for each quintile of intake. Our analysis included 347 cases diagnosed between 1984 and 2002, and 950,347 person-years of follow-up. There was no clear association between total intake of the 5 flavonoids examined and incidence of ovarian cancer (RR = 0.75 for the highest versus lowest quintile, 95% confidence interval [CI] = 0.51-1.09). However, there was a significant 40% decrease in ovarian cancer incidence for the highest versus lowest quintile of kaempferol intake (RR = 0.60, 95% CI = 0.42-0.87; p-trend = 0.002), and a significant 34% decrease in incidence for the highest versus lowest quintile of luteolin intake (RR = 0.66, 95% CI = 0.49-0.91; p-trend = 0.01). There was evidence of an inverse association with consumption of tea (nonherbal) and broccoli, the primary contributors to kaempferol intake in our population. These data suggest that dietary intake of certain flavonoids may reduce ovarian cancer risk, although additional prospective studies are needed to further evaluate this association. If confirmed, these results would provide an important target for ovarian cancer prevention.

Congenital Cytomegalovirus Infection: a Cause of Renal Dysplasia?

Pediatric and Developmental Pathology : the Official Journal of the Society for Pediatric Pathology and the Paediatric Pathology Society. Jul-Aug, 2007  |  Pubmed ID: 17638423

Cytomegalovirus (CMV) infection is one of the most frequently encountered viral infections of the fetus and induces a wide range of histologic and clinical manifestations. Congenital abnormalities are typically restricted to the central nervous system despite evidence of CMV inclusions occurring in most epithelial cells. Although tissue injury and even glomerulonephritis have been observed in congenital CMV infections, renal multicystic dysplasia has not been reported. Herein, we describe a case of unilateral renal dysplasia in a 19-week fetus with concurrent CMV infection. We believe the present case to be the first description of a virus apparently inducing renal multicystic dysplasia.

Acardiac Twin Presenting As Fetus Amorphous with an Attenuated Umbilical Cord

Pediatric and Developmental Pathology : the Official Journal of the Society for Pediatric Pathology and the Paediatric Pathology Society. Nov-Dec, 2007  |  Pubmed ID: 18001161

Acardiac anomaly sequence is a rare malformation cluster occurring in the setting of monozygotic monochorionic twin pregnancies. In addition to an absent heart (acardia), variable degrees of somatic developmental disruption are present. We describe an extreme example of what we believe to be acardiac twinning, with almost complete absence of gross tissue organization but recognizable microscopic evidence of body-axis establishment and organ formation. The case is also notable for the absence of a grossly identifiable umbilical cord, with attachment to the placental vasculature by 2 vessels invested by amnion but without Wharton's jelly. We discuss the controversy regarding the requirement of an umbilical cord in the definition of acardiac twin and distinguish this case from placental teratoma.

Do Enteric Neurons Make Hypocretin?

Regulatory Peptides. Apr, 2008  |  Pubmed ID: 18191238

Hypocretins (orexins) are wake-promoting neuropeptides produced by hypothalamic neurons. These hypocretin-producing cells are lost in people with narcolepsy, possibly due to an autoimmune attack. Prior studies described hypocretin neurons in the enteric nervous system, and these cells could be an additional target of an autoimmune process. We sought to determine whether enteric hypocretin neurons are lost in narcoleptic subjects. Even though we tried several methods (including whole mounts, sectioned tissue, pre-treatment of mice with colchicine, and the use of various primary antisera), we could not identify hypocretin-producing cells in enteric nervous tissue collected from mice or normal human subjects. These results raise doubts about whether enteric neurons produce hypocretin.

Caffeine, Alcohol, Smoking, and the Risk of Incident Epithelial Ovarian Cancer

Cancer. Mar, 2008  |  Pubmed ID: 18213613

Smoking, caffeine, and alcohol intake are all potentially modifiable factors that have an unclear association with ovarian cancer risk. Therefore, the associations between these exposures and ovarian cancer risk were prospectively examined among 110,454 women in the Nurses' Health Study (NHS) for the smoking analyses and 80,253 women for the dietary analyses.

Characterization of Chorioamnionitis in 2nd-trimester C-section Placentas and Correlation with Microorganism Recovery from Subamniotic Tissues

Pediatric and Developmental Pathology : the Official Journal of the Society for Pediatric Pathology and the Paediatric Pathology Society. Jan-Feb, 2008  |  Pubmed ID: 18237241

Prolonged exposure to infection appears to influence fetal/neonatal development. We characterize the relationship between histologic patterns of inflammation and microorganism recovery from the placentas of live born infants delivered before the 28th postmenstrual week. The subamniotic parenchyma of 835 placentas delivered by cesarean section were cultured and evaluated for specific histologic patterns of inflammation in a blinded fashion. Cases with prolonged membrane rupture were excluded. Microorganisms were recovered from 41% of placentas. Microorganisms found more frequently in placentas with high-grade chorionic plate inflammation include Actinomyces, Prevotella bivia, Corynebacterium sp., Escherichia coli, Peptostreptococcus magnus, multiple species of Streptococci, and Mycoplasma sp., including Ureaplasma urealyticum. These microorganisms were also associated with fetal vasculitis (neutrophilic infiltration of chorionic plate stem vessels or umbilical cord). Recovery of microorganisms from placental parenchyma is associated with histologic inflammation. The same microorganisms responsible for inciting high-grade chorionic plate inflammation are also most likely to promote fetal inflammation.

Colonization of Second-trimester Placenta Parenchyma

American Journal of Obstetrics and Gynecology. Jul, 2008  |  Pubmed ID: 18313635

The overtly healthy, nonpregnant uterus harbors bacteria, Mycoplasma and Ureaplasma. The extent of colonization remains elusive, as are relationships between isolated microorganisms, preterm labor and fetal inflammation.

Histologic, Surgical, and Imaging Correlations of Adnexal Masses

Journal of Ultrasound in Medicine : Official Journal of the American Institute of Ultrasound in Medicine. Mar, 2008  |  Pubmed ID: 18314510

The purpose of this study was to quantify, categorize, and illustrate discrepancies between preoperative radiologic, surgical, and pathologic diagnoses and to assess the potential impact of discrepancies on clinical care.

Assessment of Factors That Affect the Quality of Performance and Interpretation of Sonography of Adnexal Masses

Journal of Ultrasound in Medicine : Official Journal of the American Institute of Ultrasound in Medicine. May, 2008  |  Pubmed ID: 18424647

The purpose of this study was to assess factors that affect the quality of performance and interpretation of sonography of adnexal masses.

Histological Characteristics of Singleton Placentas Delivered Before the 28th Week of Gestation

Pathology. Jun, 2008  |  Pubmed ID: 18446627

The placenta is a record of the fetal environment and its examination may provide information about the baby's subsequent growth and development. We describe the histological characteristics of 947 singleton placentas from infants born between 23 and 27 weeks gestation.

Overexpression of the Alphavbeta6 Integrin in Endometrial Cancer

Applied Immunohistochemistry & Molecular Morphology : AIMM / Official Publication of the Society for Applied Immunohistochemistry. Dec, 2008  |  Pubmed ID: 18698261

The alpha(v)beta(6) integrin (alphavbeta6) has been shown to be up-regulated in adenocarcinoma of the breast, colon, stomach, and ovary, generally reflecting a more aggressive phenotype. Expression in endometrial cancer has not been reported. We analyzed alphavbeta6 expression in the tissue from primary endometrial carcinomas (endometrioid type) using a mouse monoclonal antibody against human alphavbeta6, and correlated the findings with grade, stage, and nodal involvement. Normal cycling endometrium was studied for comparison. alphavbeta6 was only weakly expressed in normal epithelium and infrequently expressed in precancers, but up-regulated in the majority of endometrial carcinomas, especially with high grade. Nodal metastases strongly expressed alphavbeta6, even when the primary tumor showed only focal expression. No correlation was found between expression and depth of invasion or the presence of metastases. Overexpression of alphavbeta6 in endometrial carcinoma is common. Expression is high in metastatic lesions. The level of expression of the primary tumor was not indicative of the presence of nodal metastasis; however, the number of cases with nodal metastases was limited.

A Comparative Analysis of Lymphatic Vessel Density in Ovarian Serous Tumors of Low Malignant Potential (borderline Tumors) with and Without Lymph Node Involvement

International Journal of Gynecological Pathology : Official Journal of the International Society of Gynecological Pathologists. Oct, 2008  |  Pubmed ID: 18753975

Lymph node involvement is seen in approximately one quarter of women with surgically staged ovarian serous tumors of low malignant potential (serous borderline tumors), and this finding apparently does not adversely impact their overall survival. To help illuminate some of the pathomechanisms underlying this novel phenomenon, in which a largely noninvasive epithelial neoplasm is able to exit its primary site and be transported to lymph nodes with such a substantial frequency, we investigated whether significant differences in lymphatic vessel density exist between ovarian serous borderline tumors that show lymph node involvement and those that do not. The lymphatic vessel density of 13 conventional ovarian serous borderline tumors (i.e. tumors without stromal microinvasion, micropapillary/cribriform areas, or invasive implants) with at least 1 positive lymph node (study group) was compared with the lymphatic vessel density of an age- and disease extent-matched control group of 13 similarly selected lymph node-negative ovarian serous borderline tumors. Lymphatic vessel density was determined by counting the total number of vascular spaces immunohistochemically stained by the lymphatic endothelium marker D2-40 in 5 consecutive microscopic fields (x20 objective, field area of 1 microscopic field, 0.95 mm) in the most vessel-dense areas and calculating the average value per microscopic field. The peritumoral lymphatic vessel density was significantly higher than the intratumoral lymphatic vessel density in both groups. However, no statistically significant differences were found between the study and control groups regarding intratumoral lymphatic vessel density (8.0 vs. 7.61; P=0.77), peritumoral lymphatic vessel density (20.33 vs. 21.0; P=0.79), or combined, that is, peritumoral plus intratumoral lymphatic vessel density (27.81 vs. 28.62; P=0.83). Our findings, in conjunction with others in the medical literature, do not support a role for tumor lymphatics in nodal metastasis in this neoplasm. We discuss the possibility that nodal deposits may represent metastatic disease from secondary tumor implants.

Validation of Tissue Microarray Technology in Ovarian Cancer: Results from the Nurses' Health Study

Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. Nov, 2008  |  Pubmed ID: 18990746

Tissue microarrays (TMAs) allow high-throughput evaluation of protein expression from archived tissue samples. We identified characteristics specific to ovarian cancer that may influence TMA interpretation.

Genomic and Functional Profiling of Human Down Syndrome Neural Progenitors Implicates S100B and Aquaporin 4 in Cell Injury

Human Molecular Genetics. Feb, 2008  |  Pubmed ID: 17984171

Down syndrome (DS) is caused by trisomy of chromosome 21 and is characterized by mental retardation, seizures and premature Alzheimer's disease. To examine neuropathological mechanisms giving rise to this disorder, we generated multiple human DS neural progenitor cell (NPC) lines from the 19-21 week frontal cortex and characterized their genomic and functional properties. Microarray profiling of DS progenitors indicated that increased levels of gene expression were not limited to chromosome 21, suggesting that increased expression of genes on chromosome 21 altered transcriptional regulation of a subset of genes throughout the entire genome. Moreover, many transcriptionally dysregulated genes were involved in cell death and oxidative stress. Network analyses suggested that upregulated expression of chromosome 21 genes such as S100B and amyloid precursor protein activated the stress response kinase pathways, and furthermore, could be linked to upregulation of the water channel aquaporin 4 (AQP4). We further demonstrate in DS NPCs that S100B is constitutively overexpressed, that overexpression leads to increased reactive oxygen species (ROS) formation and activation of stress response kinases, and that activation of this pathway results in compensatory AQP4 expression. In addition, AQP4 expression could be induced by direct exposure to ROS, and siRNA inhibition of AQP4 resulted in elevated levels of ROS following S100B exposure. Finally, elevated levels of S100B-induced ROS and loss of AQP4 expression led to increased programmed cell death. These findings suggest that dysregulation of chromosome 21 genes in DS neural progenitors leads to increased ROS and thereby alters transcriptional regulation of cytoprotective, non-chromosome 21 genes in response to ongoing cellular insults.

Disruption of Neural Progenitors Along the Ventricular and Subventricular Zones in Periventricular Heterotopia

Human Molecular Genetics. Feb, 2009  |  Pubmed ID: 18996916

Periventricular heterotopia (PH) is a disorder characterized by neuronal nodules, ectopically positioned along the lateral ventricles of the cerebral cortex. Mutations in either of two human genes, Filamin A (FLNA) or ADP-ribosylation factor guanine exchange factor 2 (ARFGEF2), cause PH (Fox et al. in 'Mutations in filamin 1 prevent migration of cerebral cortical neurons in human periventricular heterotopia'. Neuron, 21, 1315-1325, 1998; Sheen et al. in 'Mutations in ARFGEF2 implicate vesicle trafficking in neural progenitor proliferation and migration in the human cerebral cortex'. Nat. Genet., 36, 69-76, 2004). Recent studies have shown that mutations in mitogen-activated protein kinase kinase kinase-4 (Mekk4), an indirect interactor with FlnA, also lead to periventricular nodule formation in mice (Sarkisian et al. in 'MEKK4 signaling regulates filamin expression and neuronal migration'. Neuron, 52, 789-801, 2006). Here we show that neurons in post-mortem human PH brains migrated appropriately into the cortex, that periventricular nodules were primarily composed of later-born neurons, and that the neuroependyma was disrupted in all PH cases. As studied in the mouse, loss of FlnA or Big2 function in neural precursors impaired neuronal migration from the germinal zone, disrupted cell adhesion and compromised neuroepithelial integrity. Finally, the hydrocephalus with hop gait (hyh) mouse, which harbors a mutation in Napa [encoding N-ethylmaleimide-sensitive factor attachment protein alpha (alpha-SNAP)], also develops a progressive denudation of the neuroepithelium, leading to periventricular nodule formation. Previous studies have shown that Arfgef2 and Napa direct vesicle trafficking and fusion, whereas FlnA associates dynamically with the Golgi membranes during budding and trafficking of transport vesicles. Our current findings suggest that PH formation arises from a final common pathway involving disruption of vesicle trafficking, leading to impaired cell adhesion and loss of neuroependymal integrity.

Patterns of Misinterpretation of Adnexal Masses on CT and MR in an Academic Radiology Department

Academic Radiology. Aug, 2009  |  Pubmed ID: 19380241

The aim of this study was to assess potential quality assurance (QA) issues in the diagnosis and characterization of adnexal masses on pelvic computed tomographic (CT) and magnetic resonance (MR) imaging studies.

Relationship Between Epidemiologic Risk Factors and Hormone Receptor Expression in Ovarian Cancer: Results from the Nurses' Health Study

Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. May, 2009  |  Pubmed ID: 19383883

Hormone receptor expression in tumors may offer etiologic information for ovarian cancer, particularly in light of known associations with hormonal and reproductive risk factors. Tissue microarrays constructed from 157 paraffin-embedded blocks of epithelial ovarian tumors collected from participants in the Nurses' Health Study were stained for estrogen receptor-alpha (ERalpha) and progesterone receptor (PR). We examined receptor expression by invasion, grade, and histologic subtype. Multivariate unconditional logistic regression was used to evaluate whether hormonal, reproductive, and anthropometric risk factors were differentially associated with the risk of developing receptor-positive or receptor-negative ovarian tumors compared with controls. PR-expressing tumors were less likely to be invasive (P = 0.05) and more likely to be of a lower grade (P < 0.001) and stage (P = 0.007) compared with PR- tumors. ERalpha status was not associated with any pathologic features of the tumor (P > 0.34). Increasing age, being postmenopausal, and postmenopausal hormone use were associated with an increased risk of developing ERalpha+, but not ERalpha- (P(heterogeneity) = 0.001, 0.06, and 0.06, respectively) and PR-, but not PR+, tumors (P(heterogeneity) = 0.08, 0.003, and 0.40, respectively), whereas height was only associated with the risk of developing PR- disease (P(heterogeneity) = 0.08). There were no clear risk differentials with OC use, parity, body mass index, or physical activity. Reproductive and hormonal risk factors are associated with subgroups of ovarian cancer defined by histologic subtype or ERalpha and PR status. These finding support specific models of hormone mediated triggers of ovarian cancer.

Perinatal Correlates of Ureaplasma Urealyticum in Placenta Parenchyma of Singleton Pregnancies That End Before 28 Weeks of Gestation

Pediatrics. May, 2009  |  Pubmed ID: 19403499

The purpose of this work was to examine the relationship between Ureaplasma urealyticum in the placenta and perinatal outcomes in extreme preterm deliveries and to explore the influence of bacteria coinfection on perinatal outcomes in U urealyticum-positive placentas.

Invited Commentary: Intrauterine Epidemiology

American Journal of Epidemiology. Jul, 2009  |  Pubmed ID: 19509319

Traditionally, the investigation of preterm birth has relied on diagnostic definitions derived from maternal clinical presentation. However, clinical presentation may be only tangentially related to the underlying etiology of a disease. The utilization of data derived directly from the intrauterine or maternal systemic environment would be invaluable in consideration of the causes of preterm birth. In this issue, Kelly et al. (Am J Epidemiol. 2009;170(2)148-158) contribute to our understanding of the epidemiology of the intrauterine environment by classifying the vascular biology of the maternal-placental interface in cases of preterm delivery. Their histology-based approach observes that vascular conditions may be grouped into 5 constructs with specific relations to maternal and fetal vascular pathology. The frequencies of these constructs vary with regard to delivery indication and gestational age, suggesting that the intrauterine conditions associated with preterm birth are more complicated than originally appreciated. This work is laborious, and replication of the technique will be important. However, these authors have taken a large step toward introducing an "intrauterine" perspective into perinatal epidemiology and into our understanding of the underlying etiologies of preterm birth.

Retinoic Acid from the Meninges Regulates Cortical Neuron Generation

Cell. Oct, 2009  |  Pubmed ID: 19879845

Extrinsic signals controlling generation of neocortical neurons during embryonic life have been difficult to identify. In this study we demonstrate that the dorsal forebrain meninges communicate with the adjacent radial glial endfeet and influence cortical development. We took advantage of Foxc1 mutant mice with defects in forebrain meningeal formation. Foxc1 dosage and loss of meninges correlated with a dramatic reduction in both neuron and intermediate progenitor production and elongation of the neuroepithelium. Several types of experiments demonstrate that retinoic acid (RA) is the key component of this secreted activity. In addition, Rdh10- and Raldh2-expressing cells in the dorsal meninges were either reduced or absent in the Foxc1 mutants, and Rdh10 mutants had a cortical phenotype similar to the Foxc1 null mutants. Lastly, in utero RA treatment rescued the cortical phenotype in Foxc1 mutants. These results establish RA as a potent, meningeal-derived cue required for successful corticogenesis.

Risk Factors for Epithelial Ovarian Cancer by Histologic Subtype

American Journal of Epidemiology. Jan, 2010  |  Pubmed ID: 19910378

Previous epidemiologic studies suggest that the major histologic subtypes of epithelial ovarian cancer may have different risk factor profiles; however, no known prospective study has systematically examined differences in risk by subtype. The authors used Cox proportional hazards regression, stratified by histologic subtype and time period, to examine the association between ovarian cancer risk factors and incidence of serous invasive, endometrioid, and mucinous ovarian cancers in the US Nurses' Health Study (1976-2006) and Nurses' Health Study II (1989-2005). For each exposure, they calculated P-heterogeneity using a likelihood ratio test comparing models with separate estimates for the 3 subtypes versus a single estimate across subtypes. Analysis included 221,866 women and 721 cases with the histologies of interest (496 serous invasive, 139 endometrioid, 86 mucinous). In analyses of reproductive/hormonal exposures, the associations with age, duration of breastfeeding, age at natural menopause, and duration of estrogen use differed significantly by subtype (all P-heterogeneity < or =0.05). The associations with several nonreproductive exposures also appeared to vary by subtype, but only the association with smoking differed significantly (P-heterogeneity = 0.03). Results suggest that associations with several ovarian cancer risk factors vary by subtype, and these differences are consistent with known similarities between each major histologic subtype and its normal tissue counterpart.

Management of Asymptomatic Ovarian and Other Adnexal Cysts Imaged at US: Society of Radiologists in Ultrasound Consensus Conference Statement

Radiology. Sep, 2010  |  Pubmed ID: 20505067

The Society of Radiologists in Ultrasound convened a panel of specialists from gynecology, radiology, and pathology to arrive at a consensus regarding the management of ovarian and other adnexal cysts imaged sonographically in asymptomatic women. The panel met in Chicago, Ill, on October 27-28, 2009, and drafted this consensus statement. The recommendations in this statement are based on analysis of current literature and common practice strategies, and are thought to represent a reasonable approach to asymptomatic ovarian and other adnexal cysts imaged at ultrasonography.

Factors Associated with Small Head Circumference at Birth Among Infants Born Before the 28th Week

American Journal of Obstetrics and Gynecology. Aug, 2010  |  Pubmed ID: 20541727

We sought to identify risk factors for congenital microcephaly in extremely low gestational age newborns.

Antenatal Antecedents of a Small Head Circumference at Age 24-months Post-term Equivalent in a Sample of Infants Born Before the 28th Post-menstrual Week

Early Human Development. Aug, 2010  |  Pubmed ID: 20674197

Little is known about the antecedents of microcephaly in early childhood among children born at extremely low gestational age.

Management of Asymptomatic Ovarian and Other Adnexal Cysts Imaged at US Society of Radiologists in Ultrasound Consensus Conference Statement

Ultrasound Quarterly. Sep, 2010  |  Pubmed ID: 20823748

The Society of Radiologists in Ultrasound (SRU) convened a panel of specialists from gynecology, radiology, and pathology to arrive at a consensus regarding the management of ovarian and other adnexal cysts imaged sonographically in asymptomatic women. The panel met in Chicago, IL, on October 27-28, 2009, and drafted this consensus statement. The recommendations in this statement are based on analysis of current literature and common practice strategies, and are thought to represent a reasonable approach to asymptomatic ovarian and other adnexal cysts imaged at ultrasonography.

Primary Cellular Meningeal Defects Cause Neocortical Dysplasia and Dyslamination

Annals of Neurology. Oct, 2010  |  Pubmed ID: 20976766

Cortical malformations are important causes of neurological morbidity, but in many cases their etiology is poorly understood. Mice with Foxc1 mutations have cellular defects in meningeal development. We use hypomorphic and null alleles of Foxc1 to study the effect of meningeal defects on neocortical organization.

Relationship Between Dietary and Supplemental Intake of Folate, Methionine, Vitamin B6 and Folate Receptor Alpha Expression in Ovarian Tumors

International Journal of Cancer. Journal International Du Cancer. May, 2010  |  Pubmed ID: 19585555

Because folate receptor alpha (FRalpha) is frequently over-expressed in epithelial ovarian tumors, we hypothesized that its association with folate may differ by FRalpha expression or by the timing of intake. We examined the association between folate and other cofactors in 152 ovarian cancers evaluated for FRalpha expression from the Nurses' Health Study. Multivariate odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression. FRalpha expression was higher in serous invasive and advanced stage ovarian tumors. Recent dietary folate intake > or = 300 microg/day compared to < 300 microg/day was associated with decreased risk of developing ovarian cancer (OR = 0.62; 95%CI 0.40-0.96). There was suggestion of an increased risk with total folate (dietary and supplemental) (OR=1.42; 95%CI 0.94-2.14 for past and OR = 1.53; 95%CI 0.99-2.37 for recent intake). These results did not vary by FRalpha status of the tumor. Methyl group score, a marker of high dietary folate and methionine intake but low alcohol consumption, was inversely associated with risk of ovarian cancer (OR = 0.44; 95%CI 0.23-0.84 for past and OR=0.46; 95%CI 0.24-0.88 for recent intake). There were no clear individual associations between methionine, vitamin B(6), or multivitamin use and ovarian cancer risk overall or by FRalpha tumor status. Our data do not support the hypothesis that the relationship between factors involved in one-carbon metabolism and ovarian cancer risk differs by FRalpha status of the tumor.

Microbiologic and Histologic Characteristics of the Extremely Preterm Infant's Placenta Predict White Matter Damage and Later Cerebral Palsy. the ELGAN Study

Pediatric Research. Jan, 2010  |  Pubmed ID: 19745780

Inflammatory phenomena seem to contribute to the occurrence of perinatal cerebral white matter damage and CP. The stimulus that initiates the inflammation remains obscure. One thousand two hundred forty-six infants born before the 28th postmenstrual week had a protocol ultrasound scan of the brain read concordantly by two independent sonologists. Eight hundred ninety-nine of the children had a neurologic examination at approximately 24-mo postterm equivalent. The placenta of each child had been biopsied under sterile conditions and later cultured. Histologic slides of the placenta were examined specifically for this study. Recovery of a single microorganism predicted an echolucent lesion, whereas polymicrobial cultures and recovery of skin flora predicted both ventriculomegaly and an echolucent lesion. Diparetic CP was predicted by recovery of a single microorganism, multiple organisms, and skin flora. Histologic inflammation predicted ventriculomegaly and diparetic CP. The risk of ventriculomegaly associated with organism recovery was heightened when accompanied by histologic inflammation, but the risk of diparetic CP was not. Low-virulence microorganisms isolated from the placenta, including common skin microflora, predict ultrasound lesions of the brain and diparetic CP in the very preterm infant. Organism recovery does not seem to be needed for placenta inflammation to predict diparetic CP.

Myocardial Parvovirus B19 Persistence: Lack of Association with Clinicopathologic Phenotype in Adults with Heart Failure

Circulation. Heart Failure. Jan, 2011  |  Pubmed ID: 21097605

Multiple viruses have been isolated from the heart, but their significance remains controversial. We sought to determine the prevalence of cardiotropic viruses in endomyocardial biopsy (EMB) samples from adult patients with heart failure (HF) and to define the clinicopathologic profile of patients exhibiting viral positivity.

Blood Protein Profiles of Infants Born Before 28 Weeks Differ by Pregnancy Complication

American Journal of Obstetrics and Gynecology. May, 2011  |  Pubmed ID: 21349490

Disorders that lead to preterm delivery influence the fetal inflammatory response.

To Count and How to Count, That is the Question

American Journal of Clinical Pathology. Mar, 2011  |  Pubmed ID: 21350105

International Internet-based Assessment of Observer Variability for Diagnostically Challenging Endometrial Biopsies

Archives of Pathology & Laboratory Medicine. Apr, 2011  |  Pubmed ID: 21466363

Endometrial carcinoma of endometrioid histology is frequently preceded by endometrial hyperplasia, from which localized, premalignant lesions called endometrial intraepithelial neoplasia (EIN) emerge. Diagnostic criteria for EIN have been developed by histopathologic correlation with clinical outcome, molecular changes, and objective computerized histomorphometry. However, several benign mimics of EIN continue to cause diagnostic confusion.

Cluster Analysis of Placental Inflammatory Proteins Can Distinguish Preeclampsia from Preterm Labor and Premature Membrane Rupture in Singleton Deliveries Less Than 28 Weeks of Gestation

American Journal of Reproductive Immunology (New York, N.Y. : 1989). Dec, 2011  |  Pubmed ID: 21623999

Inflammation within the preterm placenta is common and leads to adverse outcomes for premature infants. The risks of complications are different between iatrogenic (e.g. PE) and spontaneous (e.g. PL and membrane rupture) causes of preterm delivery, suggesting different underlying biology contributes to these placental conditions.

Keap1 Mutations and Nrf2 Pathway Activation in Epithelial Ovarian Cancer

Cancer Research. Aug, 2011  |  Pubmed ID: 21676886

Resistance to platinum-based chemotherapy develops in the majority of patients with epithelial ovarian cancer (EOC). Platinum compounds form electrophilic intermediates that mediate DNA cross-linking and induce double-strand DNA breaks. Because the cellular response to electrophilic xenobiotics is partly mediated by Keap1-Nrf2 pathway, we evaluated the presence of Kelch-like ECH-associated protein 1 (Keap1) mutations and NF-E2-related factor 2 (Nrf2) pathway activation in EOC and correlated these with platinum resistance and clinical outcome. Nrf2 immunohistochemistry revealed nuclear localization (a surrogate of pathway activation) in over half of EOC patient specimens examined, with more common occurrence in the clear cell EOC subtype. Quantitative real-time PCR revealed that Nrf2 target genes were upregulated in tumors with nuclear positivity for Nrf2. Microarray analysis also showed upregulation of Nrf2 target genes in clear cell EOCs compared with other EOC subtypes. In addition, Keap1 sequence analysis revealed genetic mutations in 29% of clear cell samples and 8% of nonclear cell tumors. RNAi-mediated knockdown of Keap1 was associated with Nrf2 pathway activation and resistance to carboplatin in vitro. Importantly, patients with evidence of Nrf2 pathway activation had fewer complete clinical responses to platinum-based therapy, were enriched for platinum resistance, and had shorter median overall survival compared with those who did not show evidence of Nrf2 pathway activation. Our findings identify Keap1 mutations in EOC and they suggest a previously unrecognized role for the Keap1-Nrf2 pathway in mediating chemotherapeutic responses in this disease.

Stathmin 1, a Marker of PI3K Pathway Activation and Regulator of Microtubule Dynamics, is Expressed in Early Pelvic Serous Carcinomas

Gynecologic Oncology. Oct, 2011  |  Pubmed ID: 21683992

Most high-grade pelvic serous carcinomas (HGPSCs) arise from fallopian tube epithelium (FTE). To date, few markers have been shown to characterize FTE transformation. Stathmin 1 (STMN1) is a candidate oncogene whose activity is influenced by p53, p27Kip1 (p27), and PI3K/Akt pathway activation. As a microtubule destabilizing protein, STMN1 regulates cytoskeletal dynamics, cell cycle progression, mitosis, and cell migration. This study examines the expression of STMN1 and its negative regulator p27 along the morphologic continuum from normal FTE to invasive carcinoma.

Persistence After Birth of Systemic Inflammation Associated with Umbilical Cord Inflammation

Journal of Reproductive Immunology. Aug, 2011  |  Pubmed ID: 21722967

Intrauterine inflammation is followed by elevated concentrations of inflammation-related proteins in the newborn's blood. Many of these proteins have short half-lives. The persistence of this postnatal inflammation has not previously been investigated. In a sample of 834 infants born before the 28th week of gestation, 12% (103) had grade 1 or 2, and 17% (142) had grade 3, 4, or 5 umbilical cord inflammation. Concentrations of nine proteins previously shown to be associated with umbilical cord inflammation at birth were measured on the first postnatal day and at two weekly intervals after birth. We evaluated the hypothesis that children who had umbilical cord inflammation were no more likely than others to have elevated concentrations of inflammation-related proteins in postnatal blood. The concentrations of seven of the nine proteins [C-reactive protein (CRP), myeloperoxidase (MPO), IL1β, IL8, TNFα, intercellular adhesion molecule-1 (ICAM3), and matrix metalloproteinase (MMP9)] showed a tendency to be elevated on day 7 among infants with funisitis. Adjusting for gestational age, growth restriction, and three postnatal exposures (ventilation on day 7, presumed and definite early bacteremia, and Bell stage III necrotizing endocolitis) did not diminish the elevated odds ratios of concentrations in the top quartile (for gestational age and day the specimen was obtained) of MPO, IL1β, TNFα, IL8, ICAM3, and MMP9. The persistence of a relationship between umbilical cord inflammation and elevated blood concentrations of inflammation-related proteins on postnatal day 7 suggests the existence of phenomena that contribute to a reinforcement loop and thereby sustained systemic inflammation.

Placenta Microbiology and Histology and the Risk for Severe Retinopathy of Prematurity

Investigative Ophthalmology & Visual Science. Sep, 2011  |  Pubmed ID: 21775664

To test the hypothesis that the presence of bacteria and/or histologic inflammation in the placenta of infants born preterm is associated with an increased risk for severe retinopathy of prematurity (ROP).

S100B and APP Promote a Gliocentric Shift and Impaired Neurogenesis in Down Syndrome Neural Progenitors

PloS One. 2011  |  Pubmed ID: 21779383

Down syndrome (DS) is a developmental disorder associated with mental retardation (MR) and early onset Alzheimer's disease (AD). These CNS phenotypes are attributed to ongoing neuronal degeneration due to constitutive overexpression of chromosome 21 (HSA21) genes. We have previously shown that HSA21 associated S100B contributes to oxidative stress and apoptosis in DS human neural progenitors (HNPs). Here we show that DS HNPs isolated from fetal frontal cortex demonstrate not only disturbances in redox states within the mitochondria and increased levels of progenitor cell death but also transition to more gliocentric progenitor phenotypes with a consequent reduction in neuronogenesis. HSA21 associated S100B and amyloid precursor protein (APP) levels are simultaneously increased within DS HNPs, their secretions are synergistically enhanced in a paracrine fashion, and overexpressions of these proteins disrupt mitochondrial membrane potentials and redox states. HNPs show greater susceptibility to these proteins as compared to neurons, leading to cell death. Ongoing inflammation through APP and S100B overexpression further promotes a gliocentric HNPs phenotype. Thus, the loss in neuronal numbers seen in DS is not merely due to increased HNPs cell death and neurodegeneration, but also a fundamental gliocentric shift in the progenitor pool that impairs neuronal production.

Anti-Yo Antibody Associated with Occult Fallopian Tube Carcinoma

International Journal of Gynecological Pathology : Official Journal of the International Society of Gynecological Pathologists. Nov, 2011  |  Pubmed ID: 21979588

This is the case report of a 61-year-old woman who presented with progressive diplopia and ataxia. Her cerebrospinal fluid revealed high titers of anti-Yo (PCA-1) antibody and a magnetic resonance imaging with contrast showed cerebellar degeneration. Extensive imaging workup was negative for malignancy and she was otherwise asymptomatic. Given the association between anti-Yo antibodies and gynecologic malignancies, she underwent a bilateral salpingo-oophorectomy and cancer staging. Extensive section of the fimbriated end of the fallopian tube revealed a stage 1, microscopic serous adenocarcinoma. After surgery, her anti-YO titers fell and plans were made for adjuvant chemotherapy. Her neurologic symptoms are not expected to substantially improve, illustrating the urgent need for early surgical investigation in cases of paraneoplastic syndrome, even in the absence of imaging evidence of a lesion.

Relationship Between Neonatal Blood Protein Concentrations and Placenta Histologic Characteristics in Extremely Low GA Newborns

Pediatric Research. Jan, 2011  |  Pubmed ID: 20921924

Amniotic fluid infection with chorioamnionitis is associated with increased risks of morbidity and mortality in children born prematurely. These risks depend on the presence of a fetal inflammatory response. We measured the concentrations of 25 proteins in the blood of 871 infants born before the 28th wk of gestation and examined their placentas for acute inflammation. Newborns who had inflammatory lesions of the placenta were much more likely than their peers (p < 0.01) to have elevated blood concentrations of cytokines (IL-1β, IL-6, and TNF-α), chemokines (IL-8, MIP-1β, RANTES, and I-TAC), adhesion molecules (ICAM-1, ICAM-3, and E-selectin), matrix metalloproteinases (MMP-1 and MMP-9), the angiogenic inflammatory factor VEGF and its receptor VEGF-R2, and acute phase proteins (SAA and CRP) during the first 3 d after birth. In contrast, newborns with poor placental perfusion had lower levels of inflammatory proteins (p < 0.01; IL-6, RANTES, ICAM-1, ICAM-3, VCAM-1, E-selectin, MMP-1, MMP-9, MPO, and VEGF). An inverse pattern was found between newborn levels of VEGF and its competitive inhibitor VEGF-R1 in both the inflamed and poorly perfused placenta categories. These results confirm the predictive value of placental histology for the presence or absence of elevated inflammatory response in newborns.

Inflammation-related Proteins in the Blood of Extremely Low Gestational Age Newborns. The Contribution of Inflammation to the Appearance of Developmental Regulation

Cytokine. Jan, 2011  |  Pubmed ID: 20934883

We wanted to assess to what extent concentrations of circulating proteins appear to be developmentally regulated, and to what extent such regulation is influenced by intra-uterine inflammation.

Endometrial Intraepithelial Neoplasia Terminology in Practice: 4-year Experience at a Single Institution

International Journal of Gynecological Pathology : Official Journal of the International Society of Gynecological Pathologists. Mar, 2012  |  Pubmed ID: 22317874

An alternative WHO classification system for endometrial precancers and hyperplasia separates a lesion called endometrial intraepithelial neoplasia (EIN) from diffuse hormonal effects and cancer, resulting in a 3-category system. EIN is a localized lesion with objective histologic criteria, characterized by monoclonal growth of mutated cells, and associated with a 45-fold elevated cancer risk. This study summarizes our department's experience with EIN diagnoses in the 4 years since conversion to the new terminology. We identified all reports from endometrial samples diagnosed as EIN or including the terms "gland crowding" or "atypia" since conversion and obtained follow-up information from subsequent pathology specimens or clinic notes (82%). The diagnoses were reported by a mixture of pathologists, the majority of whom are not subspecialized to gynecologic pathology and the slides were not reviewed. Overall, 17.1% of women with EIN had carcinoma and 34.9% had either carcinoma or persistent EIN. The proportion of women with EIN or cancer on follow-up did not trend with years since adoption of EIN terminology. The median age at the time of diagnosis was 55 years in an overall population of women who underwent sampling at a median age of 47 years. The median follow-up time was 4 months. All cancers were of endometrioid histology; all but 2 were International Federation of Gynecology and Obstetrics grade 1. In comparison with a previous reproducibility study among expert pathologists on a comparable population from our department, these results for general pathologists show a higher false positive rate for subsequent cancer.

Antenatal Antecedents of Cognitive Impairment at 24 Months In Extremely Low Gestational Age Newborns

Pediatrics. Feb, 2012  |  Pubmed ID: 22331342

BACKGROUND AND OBJECTIVES:Extremely low gestational age neonates are more likely than term infants to develop cognitive impairment. Few studies have addressed antenatal risk factors of this condition. We identified antenatal antecedents of cognitive impairment determined by the Mental Development Index (MDI) portion of the Bayley Scales of Infant Development, Second Edition (BSID-II), at 24 months corrected age.METHODS:We studied a multicenter cohort of 921 infants born before 28 weeks of gestation during 2002 to 2004 and assessed their placentas for histologic characteristics and microorganisms. The mother was interviewed and her medical record was reviewed. At 24 months adjusted age, children were assessed with BSID-II. Multinomial logistic models were used to estimate odds ratios.RESULTS:A total of 103 infants (11%) had an MDI <55, and 99 infants (11%) had an MDI between 55 and 69. No associations were identified between organisms recovered from the placenta and developmental delay. Factors most strongly associated with MDI <55 were thrombosis of fetal vessels (OR 3.1; 95% confidence interval [CI] 1.2, 7.7), maternal BMI >30 (OR 2.0; 95% CI 1.1, 3.5), maternal education ≤12 years (OR 3.4; 95% CI 1.9, 6.2), nonwhite race (OR 2.2; 95% CI 1.3, 3.8), birth weight z score < -2 (OR 2.8; 95% CI 1.1, 6.9), and male gender (OR 2.7; 95% CI 1.6, 4.5).CONCLUSIONS:Antenatal factors, including thrombosis of fetal vessels in the placenta, severe fetal growth restriction, and maternal obesity, convey information about the risk of cognitive impairment among extremely premature newborns.

JC Virus Granule Cell Neuronopathy is Associated with VP1 C Terminus Mutants

The Journal of General Virology. Jan, 2012  |  Pubmed ID: 21940415

The polyomavirus JC (JCV) infects glial cells and causes progressive multifocal leukoencephalopathy (PML). We described a novel JCV-variant with a 10 bp deletion in the C terminus of the VP1 capsid protein, JCV(GCN1). This mutant was associated with lytic infection of cerebellar granule cell neurons and cerebellar atrophy in an human immunodeficiency virus/PML patient. This condition, also observed independently from PML, was named JCV granule cell neuronopathy (JCV GCN). We characterized JCV mutations in cerebrospinal fluid (CSF) of four other JCV GCN patients, and reviewed the literature on 10 reported cases. The strain from one patient harboured the identical GCN1-deletion, while the other patients had novel mutations in the same area, named JCV(GCN2-4), causing variable changes in VP1 structure. One patient also had wild-type JCV in the CSF. To study the mechanisms leading to JCV GCN, we compared viral replication kinetics from JCV(GCN1) with the prototype JCV(Mad1), the PML isolate JCV(HWM) and the prototype JCV(Mad1D) engineered with the GCN1-deletion. While all strains replicated at low levels in the medulloblastoma cell line DAOY from a cerebellar neuronal tumour, JCV(Mad1) replicated better in astroglial SVG cells than JCV(Mad1D) or JCV(GCN1) and all strains replicated at higher levels in COS-7 kidney cells, suggesting that the GCN1-deletion confers a disadvantage for viral growth in central nervous system white matter. The GCN1-deletion remained stable after 100 days in culture and VP1 protein was produced in all cell lines, indicating that JCV(GCN1) is replication-competent in vitro. These data highlight an important and previously overlooked aspect of JCV-pathogenesis. Detection of GCN-type JCV strains in CSF may help clinicians diagnose JCV GCN.