A multicenter randomized trial comparing a 25-gauge EUS fine-needle aspiration device with a 20-gauge EUS fine-needle biopsy device.

BACKGROUND AND AIMS: Several studies have compared EUS-guided FNA with fine-needle biopsy (FNB), but none have proven superiority. We performed a multicenter randomized controlled trial to compare the performance of a commonly used 25-gauge FNA needle with a newly designed 20-gauge FNB needle. METHODS: Consecutive patients with a solid lesion were randomized in this international multicenter study between a 25-gauge FNA (EchoTip Ultra) or a 20-gauge FNB needle (ProCore). The primary endpoint was diagnostic accuracy for malignancy and the Bethesda classification (non-diagnostic, benign, atypical, malignant). Technical success, safety, and sample quality were also assessed. Multivariable and supplementary analyses were performed to adjust for confounders. RESULTS: A total of 608 patients were allocated to FNA (n = 306) or FNB (n = 302); 312 pancreatic lesions (51%), 147 lymph nodes (24%), and 149 other lesions (25%). Technical success rate was 100% for the 25-gauge FNA and 99% for the 20-gauge FNB needle (P = .043), with no differences in adverse events. The 20-gauge FNB needle outperformed 25-gauge FNA in terms of histologic yield (77% vs 44%, P < .001), accuracy for malignancy (87% vs 78%, P = .002) and Bethesda classification (82% vs 72%, P = .002). This was robust when corrected for indication, lesion size, number of passes, and presence of an on-site pathologist (odds ratio, 3.53; 95% confidence interval, 1.55-8.56; P = .004), and did not differ among centers (P = .836). CONCLUSION: The 20-gauge FNB needle outperformed the 25-gauge FNA needle in terms of histologic yield and diagnostic accuracy. This benefit was irrespective of the indication and was consistent among participating centers, supporting the general applicability of our findings. (Clinical trial registration number: NCT02167074.).

Agreement on endoscopic ultrasonography-guided tissue specimens: Comparing a 20-G fine-needle biopsy to a 25-G fine-needle aspiration needle among academic and non-academic pathologists.

BACKGROUND AND AIM: A recently carried out randomized controlled trial showed the benefit of a novel 20-G fine-needle biopsy (FNB) over a 25-G fine-needle aspiration (FNA) needle. The current study evaluated the reproducibility of these findings among expert academic and non-academic pathologists. METHODS: This study was a side-study of the ASPRO (ASpiration versus PROcore) study. Five centers retrieved 74 (59%) consecutive FNB and 51 (41%) FNA samples from the ASPRO study according to randomization; 64 (51%) pancreatic and 61 (49%) lymph node specimens. Samples were re-reviewed by five expert academic and five non-academic pathologists and rated in terms of sample quality and diagnosis. Ratings were compared between needles, expert academic and non-academic pathologists, target lesions, and cytology versus histological specimens. RESULTS: Besides a higher diagnostic accuracy, FNB also provided for a better agreement on diagnosing malignancy (ĸ = 0.59 vs ĸ = 0.76, P < 0.001) and classification according to Bethesda (ĸ = 0.45 vs ĸ = 0.61, P < 0.001). This equally applied for expert academic and non-academic pathologists and for pancreatic and lymph node specimens. Sample quality was also rated higher for FNB, but agreement ranged from poor (ĸ = 0.04) to fair (ĸ = 0.55). Histology provided better agreement than cytology, but only when a core specimen was obtained with FNB (P = 0.004 vs P = 0.432). CONCLUSION: This study shows that the 20-G FNB outperforms the 25-G FNA needle in terms of diagnostic agreement, independent of the background and experience of the pathologist. This endorses use of the 20-G FNB needle in both expert and lower volume EUS centers.

Comparison of location of mesh placed transvaginally vs mesh placed abdominally at the time of sacrocolpopexy.

INTRODUCTION AND HYPOTHESIS: The location of mesh placed at the time of abdominal sacrocolpopexy (ASC) is hypothesized to be in the same location histologically as mesh placed via full-thickness vaginal dissection in a cadaver model. METHODS: Ten fresh frozen cadavers underwent mesh placement via traditional ASC. In the same specimen, a transvaginal mesh (TVM) procedure was performed, attempting a full-thickness dissection. A block section was excised from each area including full thickness of the vagina and bladder with the intervening mesh. This was analyzed by a blinded pathologist. RESULTS: All cadavers underwent successful placement of both transabdominal mesh and TVM. Of the abdominally placed meshes, 6 were located between the vagina and bladder, whereas 3 were situated within the vaginal wall, with an average depth of 0.30 mm. Five of the vaginal mesh pieces were placed between the bladder and vagina, and 4 within the vaginal wall at a depth of 0.25 mm. One specimen placed vaginally was 0.05 mm within the serosa of the bladder. One specimen could not be interpreted, despite multiple cuts. CONCLUSION: ASC and full-thickness vaginal dissection result in histologically similar locations. Dissection for ASC may only result in the correct plane between the bladder and vagina in approximately 60 % of cases. We achieved full-thickness dissection for the transvaginal approach in 50 % of the cases, with one small penetration into the bladder serosa. Using a full-thickness dissection technique for TVM may be one way of reducing mesh exposure rates in those seen with ASC.

Enhanced cryoprecipitate for skin graft and donor site wound healing in pigs.

Due to similarities in skin characteristics, the authors hypothesise that a pig model would most accurately show the ability of autologous, enhanced cryoprecipitate (eCryo) to improve the wound healing of split-thickness skin grafts (STSGs) and corresponding donor sites. Fifty-two STSGs (5 × 5 cm) were fashioned and treated according to a randomised protocol with an autologous eCryo-treated and a control group. Macroscopic assessment, histological evaluation and cellular composition were completed at days 7, 14, 21 and 28. Thirty-two donor sites were also created and assessed in a similar manner. Histologic analysis showed enhancement of healing over all time points for eCryo-treated donor sites. All other results showed no statistically significant improvement with the use of eCryo. Autologous cryoprecipitate appears to be a safe, inexpensive and easy-to-use alternative to fibrin glue, which carries risks and is, in many cases, prohibitively expensive. Further studies are necessary to evaluate the full potential of eCryo. Interestingly, eCryo application may improve donor site aesthetic appearance. We believe that a pig model most reliably simulates eCryo's behaviour in humans to accurately reflect its future clinical applicability.

Desmoplastic stromal response as defined by positive α-smooth muscle actin staining is predictive of invasion in adenocarcinoma of the uterine cervix.

The objective of this research was to examine the immunohistochemical profiles of adenocarcinoma in situ (AIS) and early invasive adenocarcinoma (AC) to identify biomarkers that enhance the accurate diagnosis of early invasive glandular lesions of the cervix. The University of California, Irvine, and Long Beach Memorial tumor registries were used to identify 20 women with AIS or early AC treated between 1990 and 2008. An immunohistochemical study was performed, and the primary endpoint measured was the correlation between biomarker expression and invasive disease as diagnosed on hematoxylin and eosin examination. The biomarkers studied included α-smooth muscle actin (α-SMA), estrogen receptor, carcinoembryonic antigen, Ki67, p16, cyclooxygenase-2, and cluster of differentiation 1a. Stains were described on the basis of (1) positive or negative staining; (2) intensity; (3) percentage of positive cells; and (4) pattern of staining. Statistical analysis was performed using SYSTAT v. 11.0. Fisher exact test, Mann-Whitney nonparametric test, κ statistic, and intraclass correlation coefficient were used to evaluate results and interpreter agreement. A statistically significant increase in the staining of the periglandular stroma for α-SMA was seen in AC as compared with AIS. The intensity was 2.2 versus 1.2 (P=0.04) and the percent of positive-staining cells was 44% versus 18% (P=0.05) in AC and AIS, respectively. The presence of a desmoplastic stromal response as identified by the increased periglandular staining for α-SMA is useful in identifying invasive glandular lesions of the endocervix. Further studies are necessary to establish biologically relevant cut-off values for α-SMA staining.

Differentiating squamous cell carcinoma of the cervix and epithelioid trophoblastic tumor.

BACKGROUND: Epithelioid trophoblastic tumor (ETT) is a recently described subtype of gestational trophoblastic neoplasia (GTN). Its diagnosis requires a high level of suspicion because it is often mistaken for more common cervical or uterine corpus epithelial neoplasms. CASE: This is a 39-year-old woman who presented with a cervical mass and positive human chorionic gonadotropin and was diagnosed with both locally advanced squamous cell cervical carcinoma and nonmetastatic GTN. She was treated unsuccessfully with concurrent intravenous cisplatin plus pelvic radiation and single-agent intravenous methotrexate. A retrospective review of the cervical biopsy using immunohistochemistry as well as genotyping of the tumor changed the original diagnosis to ETT. It is known that ETT is relatively unresponsive to chemotherapy compared with most other types of GTN; therefore, surgery would have been the optimal treatment. She died despite multiple salvage chemotherapies. CONCLUSIONS: Malignant GTN is one of the most curable gynecologic malignancies; however, its correct diagnosis is critical for the appropriate treatment. It can be easily misdiagnosed as a carcinoma because of their morphologic similarity. Genetic fingerprinting and immunohistochemistry are potentially valuable tools to confirm the diagnosis of ETT.

First Reported Case of Extramedullary Plasmacytoma of the Appendix.

An extramedullary plasmacytoma involving the gastrointestinal tract is extremely rare. We report an appendiceal extramedullary plasmacytoma in a 35-year-old man who presented to the emergency department because of upper abdominal pain. Computed tomography (CT) imaging revealed an incidental mass (3.7 × 1.9 × 1.6 cm) at the tip of the appendix. Microscopically, the appendix, periappendiceal soft tissue, and nearby lymph nodes were diffusely infiltrated by plasma cells that were kappa light chain restricted. Subsequent workup included an unremarkable bone marrow biopsy, as well as urine and serum electrophoresis. A diagnosis of kappa-restricted solitary extramedullary plasmacytoma was made. To our knowledge, this is the first case reported of an appendiceal extramedullary plasmacytoma in the medical literature.

A Rare Case of Ovarian Serous Borderline Tumor with Brain Metastasis.

Background. Serous borderline tumor represents a group of noninvasive tumor of the ovary bridging between benign serous cystadenoma and serous carcinoma. They are commonly seen in younger women and usually have an excellent outcome but seldom show local recurrence (J. F. Leake et al. 1991). Metastasis to the lymph nodes has rarely been reported (M. D. Chamberlin et al., 2001; M. B. Verbruggen et al., 2006). Moreover, the brain is exceptionally a rare metastatic site for ovarian tumor. There is one case of an advanced staged SBT with micropapillary pattern metastasis to the brain recently and by far it is the most distant metastasis reported (M. D. Martin et al., 2017). However, to the best of our knowledge, no report has been documented for a recurrent stage 1 typical SBT metastasizing to the brain.

Intratumor Heterogeneity of the Estrogen Receptor and the Long-term Risk of Fatal Breast Cancer.

Background: Breast cancer patients with estrogen receptor (ER)-positive disease have a continuous long-term risk for fatal breast cancer, but the biological factors influencing this risk are unknown. We aimed to determine whether high intratumor heterogeneity of ER predicts an increased long-term risk (25 years) of fatal breast cancer. Methods: The STO-3 trial enrolled 1780 postmenopausal lymph node-negative breast cancer patients randomly assigned to receive adjuvant tamoxifen vs not. The fraction of cancer cells for each ER intensity level was scored by breast cancer pathologists, and intratumor heterogeneity of ER was calculated using Rao's quadratic entropy and categorized into high and low heterogeneity using a predefined cutoff at the second tertile (67%). Long-term breast cancer-specific survival analyses by intra-tumor heterogeneity of ER were performed using Kaplan-Meier and multivariable Cox proportional hazard modeling adjusting for patient and tumor characteristics. Results: A statistically significant difference in long-term survival by high vs low intratumor heterogeneity of ER was seen for all ER-positive patients (P < .001) and for patients with luminal A subtype tumors (P = .01). In multivariable analyses, patients with high intratumor heterogeneity of ER had a twofold increased long-term risk as compared with patients with low intratumor heterogeneity (ER-positive: hazard ratio [HR] = 1.98, 95% confidence interval [CI] = 1.31 to 3.00; luminal A subtype tumors: HR = 2.43, 95% CI = 1.18 to 4.99). Conclusions: Patients with high intratumor heterogeneity of ER had an increased long-term risk of fatal breast cancer. Interestingly, a similar long-term risk increase was seen in patients with luminal A subtype tumors. Our findings suggest that intratumor heterogeneity of ER is an independent long-term prognosticator with potential to change clinical management, especially for patients with luminal A tumors.

Somatic mutations and altered expression of the candidate tumor suppressors CSNK1 epsilon, DLG1, and EDD/hHYD in mammary ductal carcinoma.

We report somatic mutations in three genes (CSNK1 epsilon, encoding the Ser/Thr kinase casein kinase I epsilon; DLG1, encoding a membrane-associated putative scaffolding protein; and EDD/hHYD, encoding a progestin induced putative ubiquitin-protein ligase) in mammary ductal carcinoma. These genes were suspected of playing a role in cancer because loss-of-function mutations in their Drosophila homologues cause excess tissue growth. Using DNA from 82 laser-microdissected tumor samples, followed by microsatellite analysis, denaturing HPLC and direct sequencing, we found multiple somatic point mutations in all three genes, and these mutations showed significant association with loss of heterozygosity of closely linked polymorphic microsatellite markers. For CSNK1 epsilon and DLG1, most of the mutations affected highly conserved residues, some were found repetitively in different patients, and no synonymous mutations were found, indicating that the observed mutations were selected in tumors and may be functionally significant. Immunohistochemical reactivity of each protein was reduced in poorly differentiated tumors, and there was a positive association between altered protein reactivity, loss of heterozygosity, and somatic mutations. There was a statistically significant association of hDlg staining with p53 and Ki67 reactivity, whereas CSK1 epsilon and EDD/hHYD staining levels were associated with progesterone receptor status. The results provide strong indications for a role of all three genes in mammary ductal carcinoma. They also justify additional studies of the functional significance of the changes, as well as a search for additional changes in these and other genes identified from studies on model systems.

Serous carcinomatous component championed by heparin-binding EGF-like growth factor (HB-EGF) predisposing to metastasis and recurrence in stage I uterine malignant mixed mullerian tumor.

The stage I uterine malignant mixed mullerian tumor (MMMT) shows different potential for progression. We reason that MMMTs with high-grade carcinomatous component and positivity for HB-EGF are prone to recurrence/metastasis in the early stage. A retrospective clinical and histopathologic review with immunohistochemical staining for HB-EGF, EGFR, and integrin-α5 was performed for 62 surgically staged MMMT cases. Recurrence/metastasis (RM) is 6/18 (33%) in stage I disease. Of all the clinicopathologic variables and biomarkers analyzed for stage I MMMT, serous carcinomatous component (83% [5/6] versus 17% [1/12], P = .0015) and HB-EGF expression (100% [6/6] versus 50% [6/12], P=.0339) were significantly different between groups with RM and without RM. The presence of serous carcinoma in all stages was 83% (5/6) in stage I with RM, 8% (1/12) in stage I without RM, 20% (1/5) in stage II, 36.4% (8/22) in stage III and 64.7% (11/17) in stage IV; this was paralleled by HB-EGF expression of 100% (6/6), 50% (6/12), 40% (2/5), 50% (11/22) and 71% (12/17) with a correlation coefficient r=0.9131 (P=.027). HB-EGF and integrin-α5 were highly expressed in MMMTs bearing serous carcinoma component, compared to endometrioid and unclassifiable/miscellaneous subtypes (84.6%/47.6%/33.3%, P=.025 for HB-EGF; and 61.5%/42.9%/20.0%, P=.021 for integrin-α5). The EGFR positivity was comparable among the three subtypes (48.1%, 47.6% and 26.7%, P=.326). This study indicates that serous carcinomatous component championed by expression of HB-EGF predisposes to recurrence/metastasis in stage I MMMT. This process might involve integrin-α5 and does not seem to require overexpression of EGFR. Further study is required.

p62 overexpression in breast tumors and regulation by prostate-derived Ets factor in breast cancer cells.

p62 is a multifunctional cytoplasmic protein able to noncovalently bind ubiquitin and several signaling proteins, suggesting a regulatory role connected to the ubiquitin-proteasome pathway. No studies to date have linked p62 protein expression with pathological states. Here we demonstrate the overabundance of p62 protein in malignant breast tissue relative to normal breast tissue. The proteasome inhibitor PSI increased p62 mRNA and protein; however, PSI treatment of breast epithelial cells transfected with the p62 promoter did not affect promoter activity. High levels of prostate-derived Ets factor (PDEF) mRNA have been identified in breast cancer compared to normal breast. Only the PSA and maspin promoters have been identified as targets of this transcription factor. Here we show that PDEF stimulates the p62 promoter through at least two sites, and likely acts as a coactivator. PSI treatment abrogates the PDEF-stimulated increase of p62 promoter activity by 50%. Thus, multiple mechanisms for the induction of p62 exist. We conclude that (1) p62 protein is overexpressed in breast cancer; (2) p62 mRNA and protein increase in response to PSI, with no change of basal promoter activity; (3) PDEF upregulates p62 promoter activity through at least two sites; and (4) PSI downregulates PDEF-induced p62 promoter activation through one of these sites.

Wnt pathway component LEF1 mediates tumor cell invasion and is expressed in human and murine breast cancers lacking ErbB2 (her-2/neu) overexpression.

This study examines the role of LEF1, a component of the Wnt signaling pathway, in human breast and murine mammary carcinoma and its relationship to ErbB2 (her-2/neu) expression. Mammary tissue and tumors from 5 different Wnt pathway-activated transgenic mouse strains and 5 different ErbB2 pathway-activated transgenic mouse strains were studied for the amount and distribution of expression of beta-catenin and LEF1. Fourteen samples of human infiltrating ductal breast cancer arising from a background of ductal carcinoma in situ (DCIS) were analyzed for LEF1, estrogen and progesterone receptor (ER and PR) and her-2/neu expression. in vitro, the effect of estradiol on LEF1 protein expression was examined in several breast cancer cell lines. The functional role of LEF1 was analyzed by a Matrigel invasion assay following transfection of breast cancer cell lines with either an LEF1 expression construct or a dominant-negative LEF1 construct. A significant (p=0.023) negative correlation between the expression of LEF1 and her-2/neu was observed in human breast cancer. LEF1 was strongly expressed, and beta-catenin had nuclear localization, in mammary tumors derived from Wnt pathway transgenic mice but not in ErbB2 pathway transgenic mice. In estrogen-receptor-positive breast cancer cell lines, LEF1 protein expression increased significantly following estradiol incubation (>200% of baseline). Following transient transfection, overexpression of LEF1 promoted and dominant-negative LEF1 inhibited tumor cell invasion. LEF1, a downstream component of the Wnt signaling pathway, defines a distinct, her-2/neu negative (non-overexpressing) subset of breast/mammary cancers in both humans and mice, mediates breast cancer cell invasion, and may be regulated in part by estradiol.

Differences in prognostic molecular markers between women over and under 45 years of age with advanced ovarian cancer.

PURPOSE: The purpose of this study was to determine whether differences in molecular markers might explain the better prognosis of women < or =45 years of age versus women >45 years of age diagnosed with ovarian cancers. EXPERIMENTAL DESIGN: Tissue sections from women with stage III-IV ovarian cancers were examined for expression of CD34, p53, and HER2. The Kaplan-Meier method and Cox Proportional Hazard analyses were used to identify predictors for outcome. RESULTS: Fifty-two women < or =45 years of age were matched with 52 women who were >45 years old. Of the 46 available tissue sections, 24 were from the younger age group (mean age, 41 years), and 22 were from the older age group (mean age, 61 years). Based on CD34 expression, tumors from women >45 years of age had lower microvessel density (MVD) compared with tumors of younger women (10.3 versus 16.1 microvessels per x400 field; P = 0.03). Lower MVD (< or =11 microvessels per x400 field) predicted for a worse prognosis than higher MVD (>11 microvessels per x400 field) in the overall study group (P = 0.001) and within the older subgroup (P = 0.03). The expressions of p53 (P = 0.13) and HER2 (P = 0.49) did not vary between the two age groups. The median survivals of those with tumors that overexpressed p53 and HER2 were 28.6 and 23.9 months compared with 51.7 and 38.6 months in those with cancers that underexpressed these markers, respectively (P = 0.09 for p53, P = 0.15 for HER2). CONCLUSIONS: Ovarian cancers in women >45 years of age had lower MVD compared with those in women < or =45 years of age. Lower MVD was an independent prognostic factor for decreased survival. Lower frequency of neovascularization in these cancers may contribute to the decreased survival observed in women >45 years of age.

Pap smears of patients with extramammary Paget's disease of the vulva.

Extramammary Paget's disease (EMPD) of the vulva is a rare entity. The diagnosis is almost always made on biopsy. Tumor cells are seen rarely in Papanicolaou (Pap) smears. We encountered three cases of EMPD that were detected in Pap smears. One patient had vulvar and vaginal involvement and the abnormal cells seen in the vaginal smear initially were interpreted as high-grade squamous intraepithelial lesion. Retrospective review showed scattered single atypical cells with enlarged hyperchromatic nuclei, coarse chromatin, inconspicuous nucleoli, high nuclear/cytoplasmic (N:C) ratio, and scanty basophilic cytoplasm. Rare signet ring cells and cells within cells were present. In the other two patients who had cervical involvement, the correct diagnosis was made on Pap smears. The slides showed both single and cohesive sheets of glandular cells with enlarged round to oval nuclei, coarse chromatin, prominent nucleoli, and abundant basophilic cytoplasm containing prominent vacuoles with signet ring-cell appearance. Cells within cells were abundant. EMPD has distinct cytomorphological features. Although infrequently encountered, EMPD can be diagnosed on Pap smears with adequate clinical history.

Cytological diagnosis of endocrine tumors of the pancreas by endoscopic ultrasound-guided fine-needle aspiration biopsy.

The aim of this study was to evaluate the efficacy and accuracy of endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) in the diagnosis of pancreatic endocrine tumors and to analyze their cytomorphology. Between March 1999 and June 2004, a total of 30 patients with a cytological diagnosis of pancreatic endocrine tumors were found. Their records were retrieved and the cytological materials were analyzed. The mean size of the tumors assessed by EUS was 3.0 cm. Immediate preliminary interpretation was rendered after an average of 1.5 passes. Based on the cellular patterns, cases were divided into three categories: loosely cohesive aggregates, discohesive single cells, and cohesive flat sheets. Most tumor cells had abundant cytoplasm and eccentric nuclei. Chromatin was fine or coarse but was evenly distributed in all cases. Nuclear pleomorphism, multinucleation, intranuclear inclusions, mitotic figures, and necrosis were seen. Immunohistochemical (IHC) studies on cell blocks confirmed the diagnosis in all cases. EUS-guided FNA is efficient and accurate in establishing the diagnosis of pancreatic endocrine tumors. The variety of cellular patterns presents several differential diagnostic issues that should be considered to avoid erroneous interpretation.

Feasibility of management of high-grade cervical lesions in a single visit: a randomized controlled trial.

CONTEXT: The incidence of cervical cancer is higher among low-income and minority women who have never undergone a conventional Papanicolaou test or who do not follow up after testing. Screening has been shown to reduce cervical cancer incidence rates. OBJECTIVES: To determine the feasibility and acceptability of immediately treating women with severely abnormal Papanicolaou test results by using a single-visit cervical cancer screening and treatment program and to compare treatment rates and 12-month follow-up rates with those of women who received usual care. DESIGN, SETTING, AND PARTICIPANTS: Randomized controlled trial conducted among 3521 women aged 18 years or older recruited between January 1999 and April 2002 at US community health centers located in predominantly Latino underserved areas. INTERVENTIONS: Women randomized to usual care (n = 1805) were discharged immediately after examination. Women randomized to the single-visit group (n = 1716) remained at the clinic until the results of their conventional Papanicolaou test were available. Large loop electrosurgical excision procedure was performed in single-visit patients with either a diagnosis of a high-grade squamous intraepithelial lesion (HGSIL)/atypical glandular cells of undetermined significance (AGUS) or suspicion of carcinoma. All other patients with abnormal Papanicolaou test results were referred to abnormal cytology clinics or elected to receive follow-up care outside the study's medical system. MAIN OUTCOME MEASURES: Treatment rates for HGSIL/AGUS at 6 months, follow-up rates at 6 months for lower-grade lesions, and 1-year follow-up rates for all patients. RESULTS: The rate of abnormal Papanicolaou test results was 4.1%. One percent of results showed high-grade lesions. In the single-visit group, the mean visit time was 2.8 hours and the mean time for delivery and processing of the Papanicolaou tests was 66 minutes. Six months after randomization, 14 (88%) of 16 single-visit and 10 (53%) of 19 usual care patients with HGSIL/AGUS had completed treatment. Fifty percent in the single-visit program and 53% of usual care with less abnormal Papanicolaou tests completed treatment within 6 months. Overall, 36% in each group presented for a follow-up Papanicolaou test 1 year later. Women in the single-visit group with high-grade lesions (10/16; 63%) were significantly more likely to attend follow-up for Papanicolaou tests 12 months later than women with similar lesions in the usual care group (4/19; 21%). CONCLUSIONS: For cervical cancer screening, the single-visit program was feasible and the degree of acceptability was high in this underserved population. Single visit programs provide an opportunity to increase the rate of immediate treatment and follow-up of women with severely abnormal Papanicolaou test results. This strategy did not improve follow-up rates for women with less-abnormal results. Trial Registration http://ClinicalTrials.govIdentifier: NCT00237562.

"Score the Core" Web-based pathologist training tool improves the accuracy of breast cancer IHC4 scoring.

Hormone receptor status is an integral component of decision-making in breast cancer management. IHC4 score is an algorithm that combines hormone receptor, HER2, and Ki-67 status to provide a semiquantitative prognostic score for breast cancer. High accuracy and low interobserver variance are important to ensure the score is accurately calculated; however, few previous efforts have been made to measure or decrease interobserver variance. We developed a Web-based training tool, called "Score the Core" (STC) using tissue microarrays to train pathologists to visually score estrogen receptor (using the 300-point H score), progesterone receptor (percent positive), and Ki-67 (percent positive). STC used a reference score calculated from a reproducible manual counting method. Pathologists in the Athena Breast Health Network and pathology residents at associated institutions completed the exercise. By using STC, pathologists improved their estrogen receptor H score and progesterone receptor and Ki-67 proportion assessment and demonstrated a good correlation between pathologist and reference scores. In addition, we collected information about pathologist performance that allowed us to compare individual pathologists and measures of agreement. Pathologists' assessment of the proportion of positive cells was closer to the reference than their assessment of the relative intensity of positive cells. Careful training and assessment should be used to ensure the accuracy of breast biomarkers. This is particularly important as breast cancer diagnostics become increasingly quantitative and reproducible. Our training tool is a novel approach for pathologist training that can serve as an important component of ongoing quality assessment and can improve the accuracy of breast cancer prognostic biomarkers.

Expression of Wnt genes and frizzled 1 and 2 receptors in normal breast epithelium and infiltrating breast carcinoma.

The Wnt genes encode a family of related, secreted proteins which initiate a signal cascade upon binding to cell surface receptor molecules. The signaling pathway has been shown to be critical for normal growth and development in model organisms and is implicated in the genesis of numerous human cancers. Wnt proteins regulate mammary development in the mouse but their precise role in normal breast development and malignant transformation in humans remains poorly defined. In this study, we have examined the expression of several Wnt ligands by in situ anti-sense RNA hybridization in normal and malignant human breast tissue, as well as in several estrogen-responsive and estrogen-independent human breast cancer cell lines. The specific Wnt genes tested included Wnt1, Wnt2, Wnt4, Wnt5a, Wnt5b, Wnt6, Wnt7b and Wnt10b. We have also studied the expression of frizzled receptors 1 and 2 by immunohistochemistry in these tissues. Our results indicate that several of the Wnt ligands, especially Wnt1 and Wnt6, are strongly expressed in both normal and malignant breast tissue and that Wnt7b is down-regulated in breast cancer, compared to normal breast epithelium. The expression of frizzled 1 and 2 receptors was found to be up-regulated in breast cancer. These studies provide additional support to the hypothesis that the Wnt signaling pathway is involved in human breast cancer.

Efficacy of cone biopsy of the uterine cervix during frozen section for the evaluation of cervical intraepithelial neoplasia grade 3.

We retrospectively selected 22 cases in which patients with a biopsy-proven diagnosis of cervical intraepithelial neoplasia grade 3 underwent cervical conization for frozen section (FS) evaluation followed by hysterectomy at the University of California Irvine Medical Center, Orange, during the August 1995 to September 9, 2001. All slides from FS and permanent section (PS) and hysterectomy specimens were reviewed. FS diagnoses were compared with those of previous biopsies, PS, and hysterectomy specimens. The PS correlated with FS in all cases but 1. Appropriate surgery was performed for all patients based on FS diagnosis. The McNemar test was used to compare the results of FS and PS, with a 2-sided P value of 1.0 and a c coefficient of 0.7755 with a 95% confidence level, indicating that the 2 groups were not significantly different. FS evaluation of cervical conization is as efficacious and accurate as evaluation of regular specimens in providing information for the appropriateness of same-day surgery. We recommend that entire tissue be submitted for FS to avoid sampling errors and to increase diagnostic accuracy.