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ContextAn increasing number of nonpalpable abnormalities requiring breast biopsy are being identified due to the widespread use of screening mammography. Large-core needle biopsy (LCNB) has become an alternative to surgical excision.ObjectiveTo determine whether LCNB is a safe and accurate technique to evaluate nonpalpable abnormalities found on breast imaging studies.Design and SettingCase series at an institutional referral center from August 1, 1991, to December 31, 1997.PatientsA total of 1643 women with 1 or more suspicious breast abnormalities received LCNBs (n=1836 lesions).InterventionThe LCNB of the breast uses a 14- or 11-gauge needle with stereotactic localization or ultrasound guidance.Main Outcome MeasureUtility and potential limitations of LCNB compared with the criterion standard, surgical excision after wire localization.ResultsOf the 1836 breast lesions sampled, 444 (24%) were found to be malignant. A total of 412 (22%) were found to be malignant on the initial LCNB and 202 repeat biopsies yielded 32 additional malignancies. Complications were infrequent: 1 patient experienced a superficial infection and 1 developed a pneumothorax after LCNB.ConclusionImage-guided LCNB is a reliable diagnostic alternative to surgical excision of suspicious nonpalpable breast abnormalities.

To describe the imaging and histologic features of large-core needle biopsy (LCNB) specimens of fibrous nodules.Of 853 breast masses in which LCNB was performed, 38 (4%) revealed histologic findings of fibrous nodules. Repeat biopsy was performed in 16 lesions (surgical excision, 13 lesions; repeat LCNB, three lesions). The mammographic and ultrasonographic findings in these 16 cases, the histologic LCNB findings, and the repeat biopsy findings were retrospectively reviewed.Repeat biopsy findings confirmed the diagnosis of fibrous nodules in 15 of the 16 masses. In one mass, repeat LCNB findings showed a fibroadenoma. The imaging features of the fibrous nodules varied. Five nodules (33%) manifested as masses with indistinct margins; six (40%), as circumscribed masses. In four cases (27%), imaging suggested malignancy. None were calcified masses. An additional 22 masses had circumscribed or indistinct borders and were diagnosed with LCNB as fibrous nodules. None of these masses had suspicious findings, and repeat biopsy was not performed.Fibrous nodules usually manifest as masses with circumscribed or indistinct margins but can have findings suggestive of malignancy. LCNB can reveal histologic findings consistent with this diagnosis. In all masses in which repeat biopsy was performed, the diagnosis of a fibrous nodule was confirmed or another benign stromal lesion was diagnosed.

PURPOSE: To classify lesions initially considered nonmalignant at large-needle core biopsy that were subsequently surgically excised or sampled at repeat biopsy. MATERIALS AND METHODS: From August 1, 1991, to December 31, 1996, 1,032 breast abnormalities (214 malignant and 818 nonmalignant lesions) were sampled at large-needle core biopsy. Of the nonmalignant lesions, 112 (14%) abnormalities were studied. Twenty-four abnormalities were subsequently excised because of discordant imaging and pathologic findings; 41 may have been missed at biopsy (25 were surgically excised, and 16 were sampled at repeat biopsy); 40 were surgically excised as recommended by the pathologist; and seven were excised for other indications. RESULTS: None of 24 abnormalities excised because of discordant findings was malignant. Among the 41 possibly missed lesions, infiltrating ductal carcinoma was found in one lesion that was removed surgically and in one sampled at repeat biopsy. Among the 40 lesions recommended for excision by the pathologist, 16 malignancies were found (ductal carcinoma in situ, 11; infiltrating ductal carcinoma, three; phyllodes tumor, two). None of the remaining seven lesions was malignant. CONCLUSION: Correlation of the technical quality of the biopsy, imaging features, and pathologic findings resulted in 96 surgical excisions and 16 repeat biopsies of lesions initially considered nonmalignant. Eighteen additional malignancies were identified.

To determine whether there are any mammographic and ultrasonographic (US) features of epidermal inclusion cysts of the breast, including heterogeneous microcalcifications, that may be used to preclude unnecessary biopsy.Clinical history and imaging findings in 15 patients who had undergone surgical excision of an epidermal inclusion cyst were reviewed.In 11 patients, imaging findings of an epidermal inclusion cyst were noted, including 10 patients with mammographic findings, one with US findings only, and seven with mammographic and US findings. The most common mammographic finding (in nine of 10 patients) was an isodense to high-density mass with a circumscribed margin; three circumscribed masses had multiple associated heterogeneous microcalcifications. In the seven patients with corresponding US findings, a circumscribed hypoechoic mass with through transmission was depicted. An additional US feature in six patients was extension of the mass into the dermis.Biopsy may be deemed unnecessary if the characteristic US and physical examination findings are present, even in the case of a cyst with heterogeneous microcalcifications.

Introduction The aim of this study was to examine the association between functional polymorphisms in the pro-inflammatory P2X7 receptor and the Ro/La autoantibody response in primary Sjögren's syndrome (pSS). Methods Twelve functional P2RX7 polymorphisms were genotyped in 114 pSS patients fulfilling the Revised American-European Consensus Criteria for pSS, and 136 controls. Genotyping of the A1405G (rs2230912) polymorphism was performed on a replication cohort consisting of 281 pSS patients and 534 controls. P2X7 receptor function in lymphocytes and monocytes was assessed by measurement of ATP-induced ethidium+ uptake. Serum IL-18 levels were determined by ELISA. Results The minor allele of P2RX7 A1405G is a tag for a common haplotype associated with gain in receptor function, as assessed by ATP-induced ethidium+ uptake. A positive association between 1405G and anti-Ro±La seropositive pSS patients was observed in Cohort 1. Although not replicated in Cohort 2, there was a consistent, significant, negative epistatic interaction effect with HLA-DR3 in seropositive pSS patients from both cohorts, thereby implicating this gain of function variant in the pathogenesis of pSS. Serum IL-18 was elevated in seropositive pSS patients, but was not influenced by P2RX7 A1405G. Conclusions The P2RX7 1405G gain-of-function haplotype may be a risk factor for seropositive pSS in a subset of subjects who do not carry HLA risk alleles, but has no effect in subjects who do (epistasis). Potential mechanisms relate to autoantigen exposure and inflammatory cytokine expression. The observed elevation of IL-18 levels is consistent with P2X7 receptor activation in seropositive pSS patients. Collectively these findings implicate P2X7 receptor function in the pathogenesis of pSS.

A case of spindle cell lipoma of the breast found on mammography in a 53-year-old woman is presented. This rare type of tumor has been previously reported on only after its presentation as a palpable mass. Radiographically it appears as a well-circumscribed mass. Ultrasonographically it appears as a homogeneously hyperechoic nodule. Histologically these lesions are composed of spindle cells intermingled with adipocytes.

In our institution for the past 4 years, stereotaxic core breast biopsy using a 14-gauge needle has been offered as an alternative to surgical excision. The purpose of this paper is to describe our protocol, results, and lessons learned from our experience.From August 1991 to July 1995, 388 stereotaxic needle core biopsies of clinically occult, noncalcified, mammographically detected solid masses were performed. In this group, 103 patients underwent subsequent surgical excision. Another 169 have had follow-up examinations 1 year or more after their biopsies.Of the 61 patients diagnosed with a malignant process on core biopsy, all had confirmation on subsequent surgical excision. Forty-one of the 42 core biopsies that showed a benign process were subsequently confirmed on surgical excision. One patient with atypical ductal hyperplasia on core biopsy had ductal carcinoma in situ on surgical excision. Patients with 169 benign masses on core biopsy have been followed for at least 1 year by mammography. Of these women, 110 have been followed for at least 2 years, and no malignant lesions have been found.Stereotaxic large-needle core biopsy appears to be an accurate alternative to surgical excision for evaluating a solid breast mass. However, the mammographic appearance, technical quality of the biopsy, and pathologic findings in each patient must be correlated to ensure the highest possible accuracy when using this technique.

A recently studied tumor antigen, MN, has been associated with cervical carcinomas and cervical intraepithelial neoplasms (CIN), suggesting that it may serve as a marker for cervical cancer or cancer risk. To determine if expression of the MN antigen paralleled parameters reflecting viral or biological events in precursor epithelium, MN expression was correlated with MIB-1 expression, morphological phenotype, and human papillomavirus (HPV) distribution and type in a series of CINs. Seventy-three percent, 62% and 83% of CIN I, II, and III, respectively, were MN antigen positive. The proportion of neoplastic cells immunoreactive for MN did not correlate with the CIN grade or with HPV types stratified by their association with cancer. Evaluation of serial sections showed no correlation between the frequency of MN antigen staining, the proportion of MIB-1 immunoreactive cells, or the proportion of HPV positive cells detected by in situ hybridization (ISH). CINs associated with prototypical high risk (HPV 16) types exhibited increased immunostaining for the MIB-1 antigen and were more often classified as HSIL in contrast to the other types. Thus, although MN expression previously has been associated strongly with squamous carcinoma, it did not emerge as a specific marker for either cancer-associated HPV types or high grade CIN. CIN I lesions associated with low and high risk HPV types were not distinguished by MIB-1 expression and viral replication. This emphasizes the interrelationship between vegetative viral functions (including viral replication) and morphological phenotype, irrespective of HPV type.

Pseudoangiomatous stromal hyperplasia is a benign, localized form of stromal overgrowth with a probable hormonal etiology. Our purpose is to describe the mammographic, sonographic, and clinical features of this entity.A retrospective review of breast imaging studies and demographic information for seven patients identified as having pseudoangiomatous stromal hyperplasia was performed. The patients were chosen from a 1-year period during which 1661 breast biopsies were performed.The patients were 36-61 years old. Six were premenopausal, and the one postmenopausal woman was on hormone replacement therapy. Three patients wee evaluated palpable breast lumps, and four were asymptomatic. All seven women had noncalcified masses that measured 1.1-11 cm and that were visible by mammography. The border characteristics were as follows: three masses were well circumscribed, two were partly circumscribed, and two were indistinct, probably because they were obscured by overlying parenchyma. Sonography was performed for five patients; lesions were visible in four. All four of these lesions were solid and circumscribed. Five of the masses had increased in size since earlier studies, and one palpable mass was found by physical examination to have grown over time. Two patients had a local recurrence of pseudoangiomatous stromal hyperplasia. Surgical excision was performed for three patients, large-core biopsy was performed for three patients, and both surgery and large-core biopsy were performed for one patient.Pseudoangiomatous stromal hyperplasia should be included in the differential diagnosis of a circumscribed or partially circumscribed mass, especially in the premenopausal population. These masses often grow over time and can recur locally. Pathologic diagnosis of the lesion may be difficult unless the pathologist is aware of the presence of a mass lesion and appreciates the stromal changes characteristic of such a lesion.

Sue Lester, Debashish Danda, Dana Cavill, Kevin Pile, Sarah Downie-Doyle, Maureen Rischmueller

The purpose of our study was to understand if Toll-like receptor 9 (TLR9) activation could contribute to the control of inflammation in Sjogren's syndrome. To this end, we manipulated TLR9 signaling in non-obese diabetic (NOD) and TLR9(-/-) mice using agonistic CpG oligonucleotide aptamers, TLR9 inhibitors, and the in-house oligonucleotide BL-7040. We then measured salivation, inflammatory response markers, and expression of proteins downstream to NF-κB activation pathways. Finally, we labeled proteins of interest in salivary gland biopsies from Sjogren's syndrome patients, compared to Sicca syndrome controls. We show that in NOD mice BL-7040 activates TLR9 to induce an alternative NF-κB activation mode resulting in increased salivation, elevated anti-inflammatory response in salivary glands, and reduced peripheral AChE activity. These effects were more prominent and also suppressible by TLR9 inhibitors in NOD mice, but TLR9(-/-) mice were resistant to the salivation-promoting effects of CpG oligonucleotides and BL-7040. Last, salivary glands from Sjogren's disease patients showed increased inflammatory and decreased anti-inflammatory biomarkers, in addition to decreased levels of alternative NF-κB pathway proteins. In summary, we have demonstrated that activation of TLR9 by BL-7040 leads to non-canonical activation of NF-κB, promoting salivary functioning and down-regulating inflammation. We propose that BL-7040 could be beneficial in treating Sjogren's syndrome and may be applicable to additional autoimmune syndromes.

In a series of nine stereotaxic large-core biopsies of calcifications, radiography of the specimen was used to ensure that appropriate tissue was removed. In eight cases, calcifications were evident at radiography as well as at histologic evaluation. Four cases were malignant and four were benign, and in one case in which calcification was not evident at either radiographic or histologic evaluation, a benign process was confirmed at surgical excision. Radiography of the specimen is a key component in diagnosis of breast calcifications sampled with large-core technique.

572 Background: The Oncotype DX recurrence score (RS) independently predicts the likelihood of benefit from adjuvant chemotherapy. However, the clinical factors that influence chemotherapy recommendations in addition to RS are not well characterized. We sought to determine how clinicians integrate the RS and standard clinicopathologic data when choosing adjuvant chemotherapy. Methods: We identified women with ER+, HER2-, LN- breast cancer seen at DFCI in whom RS testing was performed between November 2004 and October 2008. Clinical and pathological characteristics, RS and chemotherapy treatment were identified from electronic medical records. A multivariable model was used to examine which factors drove the decision to administer chemotherapy. Results: RS was performed on 269 women with the following case distribution: RS low (30) 9%. Chemotherapy was given to 7% of women with low RS, compared to 42% and 86% of women with intermediate and high RS, respectively. Tumor grade, T stage, progesterone receptor expression and RS were associated with receipt of chemotherapy in univariate analyses but age, LVI and menopausal status were not. In a multivariable logistic regression model, tumor grade, size, and RS were independent predictors of chemotherapy administration. Conclusions: Oncotype DX RS plays a critical role in medical decision making for women with early stage breast cancer at this single academic institution. However, other tumor and clinical features independently contribute to chemotherapy decisions, suggesting that tailored treatment does, and should, integrate both traditional and molecular pathological factors. [Table: see text] No significant financial relationships to disclose.

Abstract #1072 Background We have previously reported two complementary prognostic markers in breast cancer for predicting risk of recurrence (Ma et al, Clin Cancer Res, 2008): a molecular grade index (MGI) that recapitulates grade 1 and 3 tumors and stratifies grade 2 tumors, and a gene expression index (HOXB13/IL17BR or H/I) that predicts clinical outcome in estrogen receptor positive (ER+) patients and endocrine benefit (Jerevell et al, Breast Cancer Res Treat, 2007). In combination, MGI and H/I define three risk groups: Low risk (low MGI), intermediate risk (low H/I, high MGI) and high risk (high H/I, high MGI). We conducted a study to compare risk stratification by MGI and H/I within samples for which a previous recurrence score (RS) by Oncotype Dx was reported. Materials and Methods RNA was extracted from formalin-fixed paraffin-embedded sections from all obtainable samples of patients (pts) from five institutions in which a RS was reported MGH, 77pts; Brigham, 48pts; IU, 19pts; UAB, 13pts; Scripps, 9pts. Real-time RT-PCR assays for MGI and H/I were completed and binary results of low and high for both were determined using pre-defined cutpoints. Risk stratification via MGI + H/I for each sample was compared to previously reported RS's (low, intermediate or high). Results For the 166 pts, 48% had a low, 45% intermediate and 7% high RS's. Overall, risk stratifications by RS versus MGI + H/I were significantly correlated (p < 0.001) with 81% of patients with low RS also having low risk (low MGI). Risk stratification by H/I + MGI reduced intermediate risk via RS by 2.5-fold (45% versus 18%). Discussion In ER+ pts, MGI + H/I produces a significantly smaller group of patients with intermediate risk by re-stratifying a large number of patients with intermediate RS into low and high risk groups. Risk stratification by H/I + MGI in ER+ pts is by measurement of two discrete parameters: endocrine responsiveness (H/I) and proliferative status (MGI). This may allow for more informed treatment decisions by the treating oncologist. Further studies with clinical outcome are required to establish the clinical significance of these different risk stratification methods. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1072.

Resistance to amikacin among members of the family Enterobacteriaceae at a hospital in Venezuela rose from 2% in 1979 to 5% in 1984 and 10% in 1985 as amikacin usage rose 20-fold to exceed gentamicin usage. Resistance to gentamicin remained at 25 to 27%. We examined the plasmids from 21 isolates obtained in 1984 and 1985. Nine of eleven in 1984 and three of ten in 1985 carried aacA and sul on a 3.8-kb BamHI fragment of pBWH300, a 10.4-kb nonconjugative plasmid that had been mobilized into strains of six species by at least two different coresident conjugative plasmids. Six 1985 isolates of two species carried these genes on a similar BamHI fragment of the 104-kb conjugative plasmid pBWH303. One isolate in 1984 and one in 1985 carried the 69-kb conjugative plasmid pBWH301, which had aacA as the promoter-proximal gene of an operon that also encompassed the cat and aadB resistance genes. Another conjugative plasmid, pBWH302, was found in a single isolate. It carried a different aacA allele on the functional transposon Tn654, which appeared to be closely related to Tn1331, a transposon previously isolated in Argentina and Chile. Increased selection may thus have led to dissemination of an endemic aacA allele on two endemic plasmids, one spread by mobilization, with occasional intrusion of additional aacA alleles from outside.

The healthy members of a community represent its largest reservoir of bacteria resistant to antimicrobial agents. We compared the resistance to eight agents of Escherichia coli in stool samples from untreated, healthy children in cities on three continents.When screened by a selective method that detected 1 resistant colony in 10,000 colonies, nearly half the children in Boston (18 of 39) had no resistant colonies--a finding consistent with the findings of other surveys performed in developed countries. However, all but 1 of 41 children screened in Caracas, Venezuela, and all but 2 of 53 in Qin Pu, China, carried resistant strains. Only 1 child in Boston but 25 in Caracas and 34 in Qin Pu carried strains resistant to trimethoprim. None of the children in Boston or Caracas but 17 in Qin Pu carried strains resistant to gentamicin. Among 10 colonies selected randomly from each stool sample, the average frequency of resistance in Caracas was 3.6 times greater than in Boston, and that in Qin Pu was 5.3 times greater. There was resistance to five or more antimicrobial agents in 20 percent of the Qin Pu strains and in 6 percent of the Caracas strains but in none of the Boston strains.In addition to clinical isolates, as reported previously, the bacteria that colonize health children in the community may be resistant far more often in some regions than in others. A low rate of carriage of antimicrobial resistance in the community should become a public health goal.

The March 2007 issue of Arthritis Research & Therapy included a research article by Gottenberg et al[1] which reports a failure to confirm our previous study[2] of a genetic association between CTLA4 and primary Sjogrens syndrome (pSS).

Human DNA purified from HeLa cells and from three strains of skin fibroblasts was precipitated with calcium phosphate and added to mouse cells that were deficient in adenine phosphoribosyltransferase (APRT) and hypoxanthine phosphoribosyltransferase (HPRT). Selection for cells possessing either of the phosphoribosyltransferases was imposed by blocking de novo synthesis of purine nucleotides with azaserine in a medium supplemented with adenine and hypoxanthine. The frequency of colony formation after selection was 1.7 x 10(-7)-3.3 x 10(-6). Excepting some azaserine-resistant colonies that appeared only in the first experiment and infrequent revertants expressing moust APRT, all characterized clones expressed the human forms of APRT or HPRT according to the criteria of specific immunoprecipitation and electrophoretic mobility. The frequency of transfer of the human APRT gene was much greater than that of HPRT. Transfer efficiency was not significantly reduced when HeLa DNA was sheared to 6.5-13.5 kb size or when the donor DNA was isolated from a transferent that expressed human APRT.

We describe here extensive, previously unknown, genomic polymorphism in 120 regions, covering 19 autosomes and both sex chromosomes. Each contains duplication within multigene clusters. Of these, 108 are extremely polymorphic with multiple haplotypes. We used the genomic matching technique (GMT), previously used to characterise the major histocompatibility complex (MHC) and regulators of complement activation (RCA). This genome-wide extension of this technique enables the examination of many underlying cis , trans and epistatic interactions responsible for phenotypic differences especially in relation to individuality, evolution and disease susceptibility. The extent of the diversity could not have been predicted and suggests a new model of primate evolution based on conservation of polymorphism rather than de novo mutation.

Mouse-human hybrid cells that contained an inactive human X chromosome were treated with agents known to alter gene expression and to perturb DNA methylation. 5-Azacytidine greatly increased the rate of derepression of HPRT on the inactive X, while butyrate and dimethyl sulfoxide had smaller effects. Ethionine did not change the rate of derepression. Derepression of two other X-chromosomal loci, PGK and GPD, was also detected. The rate of derepression of PGK was 20-fold higher than the rate for HPRT. Derepression events at the two loci appeared to be independent. Hybrids expressing derepressed X-chromosomal genes had more variable levels of human enzyme activities when compared to control hybrids. HPRT+ clones did not appear after transfer of purified DNA from a cell hybrid containing an inactive human X into HPRT- recipients, but such clones did appear after transfer of DNA from derivative cells in which HPRT had been derepressed.

Introduction: Low copy number (CN) of the Fc gamma receptor 3B (FCGR3B) gene has been associated with systemic autoimmune disease. This receptor for IgG is present almost exclusively on neutrophils and plays a role in their interaction with immune complexes. At present the relationship between FCGR3B and rheumatoid arthritis (RA) is unclear. The aim of the present study was to investigate whether low CN of the FCGR3B gene is associated with susceptibility to RA. Method: The FCGR3B CN was determined using a custom Taqman® CN assay (Hs04211858; Applied Biosystems, Foster City, CA, USA) in 197 RA patients, recruited from a tertiary setting, and in 162 population matched controls. Odds ratios for low CN (< 2) and high CN (> 2), both relative to the normal diploid 2CN, were estimated by logistic regression. Results: A significant association between RA and low FCGR3B CN was observed, with frequencies of 13.7% in RA patients compared with 6.2% in controls (odds ratio 2.5, 95% confidence interval 1.2 to 5.4, P = 0.017). No association was observed between low CN and the presence of rheumatoid factor, anti-cyclic citrullinated peptide antibodies or radiographic erosions in RA patients. A meta-analysis including six previous studies confirmed an association between RA and low FCGR3B CN (odds ratio 1.47, 95% confidence interval 1.13 to 1.92, P = 0.004). Conclusions: The present study confirms that a low CN of the FCGR3B gene is associated with susceptibility to RA. The association may be stronger in patients recruited from a tertiary setting, which may relate to disease severity and/or complications. The mechanism of susceptibility remains unclear and further study is required.

Introduction There is evidence that early screening for pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc) improves outcomes. We compared the predictive accuracy of two recently published screening algorithms (DETECT 2013 and Australian Scleroderma Interest Group (ASIG) 2012) for SSc-associated PAH (SSc-PAH) with the commonly used European Society of Cardiology/European Respiratory Society (ESC/ERS 2009) guidelines. Methods We included 73 consecutive SSc patients with suspected PAH undergoing right heart catheterization (RHC). The three screening models were applied to each patient. For each model, contingency table analysis was used to determine sensitivity, specificity, and positive (PPV) and negative (NPV) predictive values for PAH. These properties were also evaluated in an ‘alternate scenario analysis’ in which the prevalence of PAH was set at 10%. Results RHC revealed PAH in 27 (36.9%) patients. DETECT and ASIG algorithms performed equally in predicting PAH with sensitivity and NPV of 100%. The ESC/ERS guidelines had sensitivity of 96.3% and NPV of only 91%, missing one case of PAH; these guidelines could not be applied to three patients who had absent tricuspid regurgitant (TR) jet. The ASIG algorithm had the highest specificity (54.5%). With PAH prevalence set at 10%, the NPV of the models was unchanged, but the PPV dropped to less than 20%. Conclusions In this cohort, the DETECT and ASIG algorithms out-perform the ESC/ERS guidelines, detecting all patients with PAH. The ESC/ERS guidelines have limitations in the absence of a TR jet. Ultimately, the choice of SSc-PAH screening algorithm will also depend on cost and ease of application. Electronic supplementary material The online version of this article (doi:10.1186/s13075-015-0517-5) contains supplementary material, which is available to authorized users.