Prenatal Metal Exposures and Child Social Responsiveness Scale Scores in 2 Prospective Studies.

Background: Prenatal exposure to metals is hypothesized to be associated with child autism. We aim to investigate the joint and individual effects of prenatal exposure to urine metals including lead (Pb), mercury (Hg), manganese (Mn), and selenium (Se) on child Social Responsiveness Scale (SRS) scores. Methods: We used data from 2 cohorts enriched for likelihood of autism spectrum disorder (ASD): Early Autism Risk Longitudinal Investigation (EARLI) and the Markers of Autism Risk in Babies-Learning Early Signs (MARBLES) studies. Metal concentrations were measured in urine collected during pregnancy. We used Bayesian Kernel Machine Regression and linear regression models to investigate both joint and independent associations of metals with SRS Z-scores in each cohort. We adjusted for maternal age at delivery, interpregnancy interval, maternal education, child race/ethnicity, child sex, and/or study site. Results: The final analytic sample consisted of 251 mother-child pairs. When Pb, Hg, Se, and Mn were at their 75th percentiles, there was a 0.03 increase (95% credible interval [CI]: -0.11, 0.17) in EARLI and 0.07 decrease (95% CI: -0.29, 0.15) in MARBLES in childhood SRS Z-scores, compared to when all 4 metals were at their 50th percentiles. In both cohorts, increasing concentrations of Pb were associated with increasing values of SRS Z-scores, fixing the other metals to their 50th percentiles. However, all the 95% credible intervals contained the null. Conclusions: There were no clear monotonic associations between the overall prenatal metal mixture in pregnancy and childhood SRS Z-scores at 36 months. There were also no clear associations between individual metals within this mixture and childhood SRS Z-scores at 36 months. The overall effects of the metal mixture and the individual effects of each metal within this mixture on offspring SRS Z-scores might be heterogeneous across child sex and cohort. Further studies with larger sample sizes are warranted.

Lifetime sexual violence exposure in women compromises systemic innate immune mediators associated with HIV pathogenesis: A cross-sectional analysis.

OBJECTIVES: Violence and HIV/AIDS syndemic highly prevalent among women impairs HIV prevention efforts. Prolonged exposure to violence results in physical trauma and psychological distress. Building on previous findings regarding genital immune dysregulation following sexual abuse exposure, we investigate here whether systemic changes occur as well. METHODS: Using the Women's Interagency HIV Study repository, 77 women were stratified by HIV serostatus and categorized into four subgroups: (1) no sexual abuse history and lower depression score (Control); (2) no sexual abuse history but higher depression score (Depression); (3) high sexual abuse exposure and lower depression score (Abuse); (4) high sexual abuse exposure and higher depression score (Abuse + Depression). Inflammation-associated immune biomarkers (TNF-α, IL-6, IL-1α, IL-1ß, TGF-ß, MIP-3α, IP-10, MCP-1, and Cathepsin-B) and anti-inflammatory/anti-HIV biomarkers (Secretory leukocyte protease inhibitor, Elafin, human beta-defensin-2 (HBD-2), alpha-defensins 1-3, Thrombospondin, Serpin-A1, and Cystatin-C) were measured in plasma using enzyme-linked immunosorbent assay. Within each HIV serostatus, differences in biomarker levels between subgroups were evaluated with Kruskal-Wallis and Dunn's test with Bonferroni correction. Spearman correlations between biomarkers were assessed for each subgroup. RESULTS: Compared to the Control and Depression groups, Abuse + Depression was associated with significantly higher levels of chemokines MIP-3α and IP-10 (p < 0.01) and lower levels of inflammatory cytokine IL-1ß (p < 0.01) in the HIV-uninfected population. Human beta-defensin-2 was lowest in the Abuse + Depression group (p < 0.05 versus Depression). By contrast, among HIV-infected, Abuse and Abuse + Depression were associated with lower levels of MIP-3α (p < 0.05 versus Control) and IP-10 (p < 0.05, Abuse versus Control). Inflammatory cytokine IL-6 was higher in both Abuse groups (p < 0.05 versus Control), while Elafin was lowest in the Abuse + Depression group (p < 0.01 versus Depression). CONCLUSION: We report compromised plasma immune responses that parallel previous findings in the genital mucosa, based on sexual abuse and HIV status. Systemic biomarkers may indicate trauma exposure and impact risk of HIV acquisition/transmission.

Placental methylome reveals a 22q13.33 brain regulatory gene locus associated with autism.

BACKGROUND: Autism spectrum disorder (ASD) involves complex genetics interacting with the perinatal environment, complicating the discovery of common genetic risk. The epigenetic layer of DNA methylation shows dynamic developmental changes and molecular memory of in utero experiences, particularly in placenta, a fetal tissue discarded at birth. However, current array-based methods to identify novel ASD risk genes lack coverage of the most structurally and epigenetically variable regions of the human genome. RESULTS: We use whole genome bisulfite sequencing in placenta samples from prospective ASD studies to discover a previously uncharacterized ASD risk gene, LOC105373085, renamed NHIP. Out of 134 differentially methylated regions associated with ASD in placental samples, a cluster at 22q13.33 corresponds to a 118-kb hypomethylated block that replicates in two additional cohorts. Within this locus, NHIP is functionally characterized as a nuclear peptide-encoding transcript with high expression in brain, and increased expression following neuronal differentiation or hypoxia, but decreased expression in ASD placenta and brain. NHIP overexpression increases cellular proliferation and alters expression of genes regulating synapses and neurogenesis, overlapping significantly with known ASD risk genes and NHIP-associated genes in ASD brain. A common structural variant disrupting the proximity of NHIP to a fetal brain enhancer is associated with NHIP expression and methylation levels and ASD risk, demonstrating a common genetic influence. CONCLUSIONS: Together, these results identify and initially characterize a novel environmentally responsive ASD risk gene relevant to brain development in a hitherto under-characterized region of the human genome.

Drawing out experience: Arts-informed qualitative research exploring public perceptions of community pharmacy services.

In many countries around the world, people go to community pharmacies to receive primary health care services. Awareness of public views and experiences may help to identify opportunities for greater uptake of primary health care services provided by pharmacists and ways to improve care. Arts-informed research offers the possibility to provide additional insights into public perceptions of community pharmacy services. The purpose of this exploratory study is to describe the process and results of an arts-informed research project using an adapted version of the draw and write technique in combination with focus group interviews to explore public perceptions of community pharmacy services. The draw and write technique was introduced as an introductory activity to evoke a visual expression of participants' perceptions and experiences with community pharmacy services. Participants were invited to answer the question, "What do community pharmacy services mean to you?" in the form of a drawing and words. They were then prompted to discuss their drawings in a focus group interview. This approach resulted in rich visual and textual data. Analysis consisted of a combination of manual sorting of the visual data and examination of the focus group interview data that were transcribed verbatim, anonymized, and analyzed using an inductive comparative approach. NVIVO version 12 software was used to code and manage all data. Use of the draw and write technique elicited initial, fresh perspectives about community pharmacy services prior to discussions with participants in the focus group interviews. This approach allowed researchers to access a diverse range of experiences and perspectives.

Recent sexual violence exposure is associated with immune biomarkers of HIV susceptibility in women.

PROBLEM: HIV/AIDS and sexual violence act synergistically and compromise women's health. Yet, immuno-biological mechanisms linking sexual violence and increased HIV susceptibility are poorly understood. METHODS: We conducted a cross-sectional pilot study of HIV-uninfected women, comparing 13 women exposed to forced vaginal penetration within the past 12 weeks (Exposed) with 25 Non-Exposed women. ELISA assays were conducted for 49 biomarkers associated with HIV pathogenesis in plasma and cervicovaginal lavage (CVL). Differences between Exposed and Non-Exposed were analyzed by linear and logistic regression, using propensity score weighting to control for age, race, socioeconomic status, menstrual cycle, and contraceptive use. RESULTS: In CVL, Exposed women had significantly reduced chemokines MIP-3α (p < .01), MCP-1 (p < .01), and anti-HIV/wound-healing thrombospondin-1 (p = .03). They also had significantly increased inflammatory cytokine IL-1α (p < 0.01) and were more likely to have detectable wound-healing PDGF (p = .02). In plasma, Exposed women had reduced chemokines MIP-3α (p < .01) and IL-8 (p < .01), anti-inflammatory cytokine TGF-ß (p = .02), anti-HIV/antimicrobial HBD-2 (p = .02), and wound-healing MMP-1 (p = 0.02). They also had increased thrombospondin-1 (p < .01) and Cathepsin B (p = .01). After applying the stringent method of false discovery rate adjustment, differences for IL-1α (p = .05) and MCP-1 (p = .03) in CVL and MIP-3α (p = .03) in plasma remained significant. CONCLUSIONS: We report systemic and mucosal immune dysregulation in women exposed to sexual violence. As these biomarkers have been associated with HIV pathogenesis, dysregulation may increase HIV susceptibility.

Cross comparison of AmpFire HPV genotyping assay and Roche human papillomavirus (HPV) linear array for HPV genotyping of anal swab samples.

Although anal cancers represent just 0.5 % of all new cancer cases in U.S., rates have increased markedly, with highest rates in HIV-infected MSM. American Cancer Society estimates there will be ∼9090 new cases and ∼1420 deaths in 2021. We compared Roche Linear Array HPV Genotyping (Roche) and AmpFire HPV Genotyping (AmpFire) assays for concordance and agreement to detect 15 hr-HPV types from 151 anal specimens. Within run precision of AmpFire was assessed on 50 anal specimens. Specimens with Roche Combo-positive and HPV33, HPV35 and/or HPV58-positive results were further tested using HPV52-specific TaqMan assay. AmpFire generated valid results on 149/151 (98.7 %) specimens; 135/149 (90.6 %) and 134/149 (89.9 %) had detectable HR-HPV DNA by AmpFire or Roche, respectively. Overall concordance was 89.8 % (2007/2235, κ = 0.65). HPV16 showed highest overall concordance at 93.3 % (139/149, κ = 0.84). HPV68 had lowest overall concordance at 77.2 % (115/149, κ = 0.28). Kappa values were interpreted as being moderate or good for all other HR-HPV types. Within run precision generated 744/750 concordant results; R2 value = 0.97 (p < 0.0001) (Mantel Test). In conclusion, AmpFire and Roche demonstrated good inter-assay agreement for detecting most HR-HPV types from anal samples, with AmpFire detecting a broader range of HPV68 subtypes and detecting HPV52 without the need for confirmatory testing.

Vitamin D Status Impacts Genital Mucosal Immunity and Markers of HIV-1 Susceptibility in Women.

While vitamin D insufficiency is known to impact a multitude of health outcomes, including HIV-1, little is known about the role of vitamin D-mediated immune regulation in the female reproductive tract (FRT). We performed a pilot clinical study of 20 women with circulating 25(OH)D levels <62.5 nmol/L. Participants were randomized into either weekly or daily high-dose oral vitamin D supplementation groups. In addition to serum vitamin D levels, genital mucosal endpoints, including soluble mediators, immune cell populations, gene expression, and ex vivo HIV-1 infection, were assessed. While systemic vitamin D levels showed a significant increase following supplementation, these changes translated into modest effects on the cervicovaginal factors studied. Paradoxically, post-supplementation vitamin D levels were decreased in cervicovaginal fluids. Given the strong correlation between vitamin D status and HIV-1 infection and the widespread nature of vitamin D deficiency, further understanding of the role of vitamin D immunoregulation in the female reproductive tract is important.

Dysregulation in Genital Tract Soluble Immune Mediators in Postmenopausal Women Is Distinct by HIV Status.

A rise in new HIV diagnoses among older adults is characterized by poor prognosis and reduced survival times. Although heterosexual transmission remains the main route of infection in women, little is known regarding immune functions in the genital tract of postmenopausal women, especially those who are HIV positive. Furthermore, effects of hormone replacement therapy (HRT) on the genital tract immune system are unclear. Using the Women's Interagency HIV Study repository, we obtained cervical-vaginal lavage (CVL) samples from premenopausal and postmenopausal HIV-positive and HIV-negative women, some of whom were on HRT. Samples were assayed for interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-α, secretory leukocyte protease inhibitor (SLPI), Elafin, human beta defensin-2 (HBD2), and macrophage inflammatory protein (MIP)-3α using ELISA. Anti-HIV activity in CVL was measured using TZM-bl indicator cells. Among HIV-positive women, the plasma viral load was significantly higher and CD4 count was significantly lower in postmenopausal compared with premenopausal women. Postmenopausal women, irrespective of HIV status, had significantly lower levels of HBD2 compared with premenopausal women. Among the HIV-negative individuals, postmenopausal women had significantly lower levels of MIP-3α, IL-6, and SLPI compared with premenopausal women. In contrast, HIV-positive postmenopausal women had significantly higher levels of TNF-α compared with HIV-positive premenopausal women. In most cases, HRT groups resembled the postmenopausal groups. No significant differences in anti-HIV activity by menopausal or by HIV status were noted. Our findings indicate that the female genital tract immune microenvironment is distinct by menopausal status and HIV status. Further studies are needed to assess the risk of HIV acquisition/transmission in this population.

Pharmacists' learning needs in the era of expanding scopes of practice: Evolving practices and changing needs.

BACKGROUND: Continuing professional development fosters advancement in knowledge and skills and can support changes in practice. Research suggests that pharmacists perceive the need for additional training to take on expanded roles. However, the types of professional development and preferred learning methods are unclear. OBJECTIVE: To identify pharmacists' professional learning needs in order to support expanded roles in practice. METHODS: A mixed-methods approach was used. In focus groups made up of pharmacists and pharmacy students, learning needs associated with their perceptions of pharmacists' roles were examined. A web-based survey of Albertan pharmacists determined the knowledge, experience, and confidence required to engage in professional activities, preferred learning methods, and professional development needed to support pharmacists currently and in future. RESULTS: Analysis of data obtained from 5 focus groups (n = 42) revealed learning needs related to changes in pharmacists' roles. Pharmacists valued the social aspect of learning as well as the role of certification in building confidence. Survey data (n = 416) indicated that a high proportion of pharmacists reported training needs in the areas of physical assessment, interpreting laboratory tests, and making decisions about complex drug therapy. Community pharmacists and those with bachelor degrees were more likely to indicate a need for additional training in various patient care skills. Pharmacists reported a preference for learning with peers and learning at work within teams. CONCLUSION: Meeting various learning needs will foster pharmacists in their current and future professional roles, including situated learning in the workplace. These findings will be of interest to employers and educators in supporting pharmacists' evolving roles in practice.

Impact of chronic sexual abuse and depression on inflammation and wound healing in the female reproductive tract of HIV-uninfected and HIV-infected women.

Sexual violence is associated with increased risk of HIV acquisition/transmission in women. Forced sex can result in physical trauma to the reproductive tract as well as severe psychological distress. However, immuno-biological mechanisms linking sexual violence and HIV susceptibility are incompletely understood. Using the Women's Interagency HIV Study repository, a total of 77 women were selected to form 4 groups, stratified by HIV serostatus, in the following categories: 1) no sexual abuse history and low depressive symptom score (below clinically significant cut-off, scores <16) (Control); 2) no sexual abuse history but high depressive symptom score, ≥16 (Depression); 3) chronic sexual abuse exposure and low depressive symptom score (Abuse); 4) chronic sexual abuse exposure and high depressive symptom score (Abuse+Depression). Inflammation-associated cytokines/chemokines/proteases (TNF-α, IL-6, IL-1α, IL-1ß, TGF-ß MIP-3α, IP-10, MCP-1, Cathepsin B), anti-inflammatory/anti-HIV mediators (Secretory leukocyte protease inhibitor (SLPI), Elafin, beta defensin 2 (HBD2), alpha defensins (HNP 1-3), Thrombospondin (TSP-1), Serpin A1, A5, Cystatin A, B), and wound-healing mediators (Gro-α, VEGF, PDGF, EGF, FGF, IGF), were measured in cervical-vaginal lavage (CVL) using ELISA. Linear regression was used to model association of biomarkers with depression and abuse as predictor variables; the interaction between depression and abuse was also tested. Anti-HIV activity in CVL was tested using TZM-bl indicator cell line. In HIV-uninfected women, median levels of IL-6 (p = 0.04), IL-1α (p<0.01), TGF-ß (p = 0.01), IP-10 (p = <0.01), PDGF (p<0.01) and FGF (p<0.01), differed significantly between groups. Specifically, an association was found between chronic sexual abuse and increased IL-1α (p<0.01), MIP-3α (p = 0.04), IP-10 (p<0.01), Serpin B1 (p = 0.01), FGF (p = 0.04) and decreased TGF-ß (p<0.01), MCP-1 (p = 0.02), PDGF (p<0.01). Further, there was evidence of significant interactions between chronic sexual abuse and current depression for IL-1α, IP-10, Serpin A1, Cystatin B, and FGF. In HIV-infected women, median levels of TNF-α (p<0.01), IL-6 (p = 0.05), MIP-3α (p<0.01), and MCP-1 (p = 0.01), differed significantly between groups. Specifically, an association was found between chronic sexual abuse and increased MCP-1 (p = 0.03), Gro-α (p = 0.01) and decreased TNF-α (p<0.01), IL-1α (p = 0.02), MIP-3α (p<0.01) and Cathepsin B (p = 0.03). Current depressive symptoms were associated with significantly decreased MIP-3α (p<0.01). There was evidence of significant interactions between chronic sexual abuse and current depression for MCP-1 and FGF. No significant differences were observed in anti-HIV activity among all eight groups. Heat-map analyses revealed distinct immune network patterns, particularly in the Abuse groups for both HIV-infected and uninfected women. Our data indicates a complex relationship between chronic sexual abuse exposure, depressive symptoms, and FRT immune mediators that are also affected by HIV status. Association of chronic sexual abuse with increase in inflammation-associated cytokine/chemokine expression, along with impaired wound-healing associated growth-factors can create a microenvironment that can facilitate HIV infection. Evaluation of longitudinal changes in exposures and biomarkers are needed to untangle the immuno-biological mechanisms that may put women who endure life-long sexual abuse at increased risk for HIV.

Immune biomarkers and anti-HIV activity in the reproductive tract of sexually active and sexually inactive adolescent girls.

PROBLEM: Adolescent girls are disproportionately affected by the HIV/AIDS pandemic, accounting for 22% of all new HIV infections globally. Yet little is known regarding the immune microenvironment of the adolescent female reproductive tract, especially regarding differences among sexually active and inactive girls, a critical parameter to evaluate HIV susceptibility associated with young age and sexual debut. METHODS: Cervico-vaginal lavage (CVL) was collected from sexually active (10) and inactive (8) girls aged 11-19 years and analyzed by ELISA for inflammation-associated biomarkers IL-6, IL-8, TNF-α, MIP-3α, IL-1α, IL-1ß, matrix metalloproteinases (MMP) 1, 2, 7, 8, and 9, as well as anti-HIV mediators, Elafin, SLPI, human beta-defensin 2, and tissue inhibitor of matrix metalloproteinases (TIMP) 1 and 2. Cervical ectopy was analyzed using Volocity. Anti-HIV activity was determined by TZM-bl assay. Statistical analyses were performed using GraphPad Prism and R. RESULTS: Sexually inactive girls had significantly higher levels of TNF-α (P = .029) in CVL compared to sexually active girls. In contrast, sexually active girls showed a trend toward higher levels of IL-1α (P = .051) compared to the sexually inactive girls. Heat-map correlations between cervical ectopy and immune biomarkers were also distinct between the 2 populations with significant positive associations between % ectopy and inflammation-associated biomarkers IL-6, IL-1ß, IL-8, MIP-3α, MMP-8, and MMP-9 observed in the sexually inactive but not sexually active group. CONCLUSION: Higher pro-inflammatory biomarker TNF-α, as well as a distinct inflammation-associated immune clustering in sexually inactive girls, can potentially increase risk for infections including HIV upon sexual debut. Future studies with larger sample sizes are needed to characterize the immune parameters associated with sexual activity.

Comparison of sample types and diagnostic methods for in vivo detection of Mycoplasma hyopneumoniae during early stages of infection.

Detection of Mycoplasma hyopneumoniae in live pigs during the early stages of infection is critical for timely implementation of control measures, but is technically challenging. This study compared the sensitivity of various sample types and diagnostic methods for detection of M. hyopneumoniae during the first 28days after experimental exposure. Twenty-one 8-week old pigs were intra-tracheally inoculated on day 0 with M. hyopneumoniae strain 232. Two age matched pigs were mock inoculated and maintained as negative controls. On post-inoculation days 0, 2, 5, 9, 14, 21 and 28, nasal swabs, laryngeal swabs, tracheobronchial lavage fluid, and blood samples were obtained from each pig and oral fluid samples were obtained from each room in which pigs were housed. Serum samples were assayed by ELISA for IgM and IgG M. hyopneumoniae antibodies and C-reactive protein. All other samples were tested for M. hyopneumoniae DNA by species-specific real-time PCR. Serum antibodies (IgG) to M. hyopneumoniae were detected in challenge-inoculated pigs on days 21 and 28. M. hyopneumoniae DNA was detected in samples from experimentally inoculated pigs beginning at 5days post-inoculation. Laryngeal swabs at all samplings beginning on day 5 showed the highest sensitivity for M. hyopneumoniae DNA Detection, while oral fluids showed the lowest sensitivity. Although laryngeal swabs are not considered the typical M. hyopneumoniae diagnostic sample, under the conditions of this study laryngeal swabs tested by PCR proved to be a practical and reliable diagnostic sample for M. hyopneumoniae detection in vivo during early-stage infection.

Perceptions of pharmacists' roles in the era of expanding scopes of practice.

BACKGROUND: Alberta was the first province in Canada to enact legislative changes to permit expansion of pharmacists' scope of practice, including allowing pharmacists to prescribe. However, such changes to the scope of practice can blur professional boundaries and obscure the roles of pharmacists. Understanding perceptions about the pharmacist's role may provide insight into recent and historical changes in pharmacy practice. This study clarifies perceptions held by pharmacists and other stakeholders concerning the role of the pharmacist in society. OBJECTIVE: To understand the perceptions of pharmacists, pharmacy students, technicians, other health care professionals, and the public of the pharmacist's role in Alberta. METHODS: A mixed methods approach was used: focus group sessions (n = 9) and individual interviews (n = 4) of pharmacists and other stakeholders were conducted and analyzed using qualitative-descriptive approach. A web-based survey of Alberta pharmacists (n = 416) explored pharmacists' perceptions of their own roles. RESULTS: Data analysis revealed the following: participants perceived that the pharmacist's role was transitioning to focus more on patient care; consistency in pharmacist uptake of this new role shaped the public's expectations; pharmacists with expanded scopes of practice were assuming greater responsibility; collaboration and relationships with other health care professionals were essential. The survey confirmed that changes in the roles of pharmacists were primarily related to patient care. CONCLUSION: Following legislative changes and implementation of a compensation framework for pharmacy services, pharmacists and other stakeholders perceived the pharmacist's role to be shifting toward patient care. Periodic revisiting of pharmacists' roles and professional activities is needed to evaluate changes over time.

Older adults with hoarding behaviour aging in place: looking to a collaborative community-based planning approach for solutions.

This paper reports on and synthesizes new research that examines how a collaborative community response can promote successful aging in place for older adults with hoarding behaviour. Through interviews with older adults with hoarding behaviour, who used a particular community support and a focus group interview with members of the community collaborative that directed supports for this population, our findings suggest that there were valuable outcomes for both groups. These older adults with hoarding behaviour were able to remain in their own homes, their safety was enhanced, their sense of isolation was minimized, empowerment was fostered, and they gained valuable insight into their behaviour. The members of the community collaborative were able to access the expertise of other professionals, maximize their own expertise, and they generated an enhanced understanding of the experience of older adults living with hoarding behaviour in Edmonton. This study is a significant addition to the much too sparse literature about the community planning needs of older adults with hoarding behaviour. It offers knowledge that is integral to theories and principles of better aging in place but attempts to translate this into practice.

Patient- and cyst-related factors for improved prediction of malignancy within cystic lesions of the pancreas.

BACKGROUND AND AIMS: Early diagnosis of cancer in pancreatic cysts is important for timely referral to surgery. The aim of this study was to develop a predictive model for pancreatic cyst malignancy to improve patient selection for surgical resection. METHODS: We performed retrospective analyses of endoscopic ultrasound (EUS) and pathology databases identifying pancreatic cysts with available final pathological diagnoses. Main-duct intraductal papillary mucinous neoplasms (IPMNs) were excluded due to the clear indication for surgery. Patient demographics and symptoms, cyst morphology, and cyst fluid characteristics were studied as candidate risk factors for malignancy. RESULTS: 270 patients with pancreatic cysts were identified and analyzed (41% men, mean age 61.8 years). Final pathological diagnoses were branch-duct IPMN (n = 118, 50% malignant), serous cystadenoma (n = 71), pseudocyst (n = 37), mucinous cyst adenoma/adenocarcinoma (n = 36), islet cell tumor (n = 4), simple cyst (n = 3), and ductal adenocarcinoma with cystic degeneration (n = 1). Optimal cut-off points for surgical resection were cyst fluid carcinoembryonic antigen (CEA) > or =3,594 ng/ml, age >50, and cyst size >1.5 cm. Cyst malignancy was independently associated with white race (OR = 4.1, p = 0.002), weight loss (OR = 3.9, p = 0.001), cyst size >1.5 cm (OR = 2.4, p = 0.012), and high CEA > or =3,594 (OR = 5.3, p = 0.04). In white patients >50 years old presenting with weight loss and cyst size >1.5 cm, the likelihood of malignancy was nearly sixfold greater than in those patients who had none of these factors (OR = 5.8, 95% CI = 2.1-16.1, p = 0.004). CONCLUSIONS: Risk factors other than cyst size are important for determination of malignancy in pancreatic cysts. Exceptionally high cyst fluid CEA levels and certain patient-related factors may help to better predict cyst malignancy and the need for surgical treatment.

Immunostaining of plasma cells in primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease characterized by inflammatory destruction of the intrahepatic bile ducts. The differential diagnosis for PBC often includes autoimmune hepatitis (AIH). Both diseases can show prominent plasma cells and other overlapping histologic features. It is interesting that both diseases can involve elevated levels of serum immunoglobulins, with IgM elevations typical of PBC and IgG elevations typical of AIH. We investigated whether this difference could be useful histologically by immunostaining plasma cells in liver biopsy specimens for IgG and IgM. We examined 56 cases: 18 of PBC and 38 of AIH. In PBC, plasma cells in the portal tracts were predominantly IgM+, whereas in AIH, plasma cells were predominately IgG+ (P < .0001). Immunostaining for IgM and IgG can be helpful in differentiating PBC from AIH.

Hepatitis in common variable immunodeficiency.

Common variable immunodeficiency is an important form of primary immunodeficiency disease. The most recognized histologic manifestation of common variable immunodeficiency is a paucity of plasma cells in gut biopsies. However, chronic inflammation can affect other organs including the liver. This study was designed to characterize the histologic findings in liver biopsies of individuals with common variable immunodeficiency. Thirteen liver biopsies from 10 patients were identified. The most common indication for biopsy was elevated liver enzymes, hepatomegaly, and/or splenomegaly. The biopsies typically showed mild portal and mild-to-moderate lobular chronic inflammation with minimal or absent interface activity. Plasma cells were absent in all cases. The biopsy specimens showed no fibrosis (n = 5) or mild portal fibrosis (n = 5). In 2 patients with follow-up biopsies, no fibrosis progression was identified. Four individuals showed small numbers of scattered portal and/or lobular granulomas, 3 of whom had diagnoses of coexistent sarcoidosis. Overall, the inflammatory changes in the biopsies were reminiscent of those seen in individuals with chronic inflammation of the gut, which can lead to translocation of intestinal luminal antigens to the liver and a mild hepatitis. Subsequent review of concurrent intestinal biopsies available in 7 individuals showed intestinal inflammation in 5 of 7 cases. In conclusion, liver biopsies in individuals with common variable immunodeficiency show mild portal and lobular inflammation with no or mild portal fibrosis. The etiology of the common variable immunodeficiency hepatitis remains unclear but, in some cases, may be secondary to mucosal inflammation in the gastrointestinal tract.

Expression of melanoma antigens in epithelioid gastrointestinal stromal tumors: a potential diagnostic pitfall.

CONTEXT: Most gastric gastrointestinal stromal tumors (GISTs) express CD117/c-kit, as do a subset of metastatic melanomas, leading to a diagnostic dilemma in some cases. OBJECTIVE: To further differentiate GISTs from melanoma, we investigated expression of melanoma markers in GISTs using a well-characterized set of gastric lesions on tissue microarrays. DESIGN: Tissue microarrays from paraffin-embedded tissue cores from 38 patients were stained with S100 protein, HMB-45, and Melan-A antibodies. All cases had been previously stained with CD117/c-kit and CD34 antibodies. All were reactive with CD117/c-kit, and 88.2% expressed CD34. RESULTS: S100 protein was focally expressed in 2 (5.3%) of 38 GISTs; these lesions lacked HMB-45 and Melan-A labeling. No tumor labeled with HMB-45, but 4 (10.6%) of 38 cases labeled with Melan-A antibodies. The Melan-A-reactive cases were all S100 negative and CD34 positive. The S100-reactive cases were spindle cell neoplasms, whereas the Melan-A-reactive cases were epithelioid neoplasms (4/9; 44%). An additional 15 standard sections of separate cases of epithelioid GISTs were then labeled with Melan-A, and 5 (33%) of 15 showed at least focal labeling. CONCLUSIONS: Melan-A staining can be encountered in a subset of epithelioid GISTs, a finding that can suggest a differential diagnosis of melanoma. In this series, the Melan-A-reactive cases lacked S100 protein and expressed CD34, both of which would be unlikely in melanoma. As such, a panel approach is best in differentiating epithelioid GISTs from melanoma.

Molecular characterization of pancreatic neoplasms.

Molecular analyses of neoplasms of the pancreas, coupled with careful histopathologic examination has helped refine the classification of pancreatic neoplasia. A number of molecularly and histologically distinct subtypes of pancreatic neoplasms have been identified and, importantly, many of these subtypes have important clinical implications. For example, most of the solid-pseudopapillary neoplasms harbor mutations in the beta-catenin gene (CTNNB1), and, as a result, most solid-pseudopapillary neoplasms have an abnormal nuclear pattern of labeling with antibodies to the beta-catenin protein. Clinically, patients with a solid-pseudopapillary neoplasm have a much better prognosis than do patients with ductal adenocarcinoma of the pancreas. Therefore, the immunolabeling of a pancreatic biopsy for the beta-catenin protein can help identify patients with low-risk neoplasms. It is clear that the time is now ripe for a new modern classification of neoplasms of the pancreas; a classification that does not abandon gross and microscopic pathology, but which instead integrates molecular findings with gross, microscopic, and clinical findings.

Gastrointestinal tract epithelial changes associated with taxanes: marker of drug toxicity versus effect.

BACKGROUND: Microscopic findings associated with paclitaxel (Taxol) chemotherapy toxicity were described years ago but whether they are specific for toxicity remains unclear. Further, epithelial changes associated with taxanes can mimic high-grade dysplasia (HGD) in non-neoplastic gastrointestinal (GI) tract mucosa. Similar changes associated with colchicine are only seen in patients with toxicity. METHODS: GI tract specimens were reviewed (221 total; 93 esophageal, 55 gastric cardiac, 48 oxyntic, 7 antral, 8 small bowel, 6 colonic, 3 appendiceal, 1 anal) from 71 patients (63M, 8F), 38 to 84 years (median, 55 y) undergoing chemotherapy for esophageal, breast, or lung cancer who had all received taxanes at some time [either paclitaxel (Taxol, 55 patients) or docetaxel (Taxotere, 16 patients)]. Epithelial changes (mitotic arrest/ring mitoses, apoptosis) associated with taxanes were graded on a scale of 0 to 3 (0=no mitotic arrest; 1=rare arrest; 2=scattered arrest; 3=striking mitotic arrest and apoptosis). Samples from the patients taken before administration of taxanes were also reviewed; all samples were reviewed without knowledge of the interval between drug doses and the biopsy/resection. RESULTS: Five samples had striking mitotic arrest mimicking HGD in non-neoplastic mucosa and were from the esophagus, gastric cardia, gastric body, gastric antrum, and appendix of 5 separate patients. All 5 had GI tract samples obtained 1 to 3 days after taxane administration. These patients had all taken Taxol (rather than Taxotere). On follow-up, in 3/5 patients with samples 1 day posttreatment, 1 had acute appendicitis (died 180 d postappendectomy), 1 died a day later of metastases, and 1 was asymptomatic (alive with metastatic disease at 126 d postbiopsy). The remaining 2 died of metastases at 90 and 210 days postbiopsy with no signs of drug toxicity at any time. CONCLUSIONS: In contrast to colchicine-associated changes in non-neoplastic mucosa, the mitotic arrest mimicking HGD seen in GI tract specimens after taxane administration is not specific for toxicity, but may also reflect taxane effect. It can be encountered in asymptomatic patients who have recently had medication. If these findings are seen histologically, they merit correlation with the clinical impression, and should not be interpreted as toxicity in isolation.