bluuebunny/crossref_metadata_2025_split huggingface dataset:
N-ethoxybenzylimidazoles: a novel acid-sensitive linker for controlled release of therapeutics from drug delivery systems.
Authors: Luong A , Issarapanichkit T , Yang JC 
Published: December 2010

Abstract
Abstract #2156
Background:&#x2028; Drug delivery systems (DDS) are useful for cancer therapies because they can target tumors and cancer cells more specifically than cancer therapeutics alone. An important component of a DDS is the triggering mechanism for drug release. This presentation will highlight a new class of N-linked imidazoles as potential acid-sensitive cleavable linkers for use in cancer DDSs. These acid-sensitive linkers are designed to exploit the lower extracellular pH of some tumors and the endosomes and lysosomes within cells to trigger the controlled release of therapeutic agents from drug delivery vessels. Cleavage of N-ethoxybenzylimidazoles (NEBIs) exhibit a 10-fold increase in the rate of hydrolysis in mild aqueous acidic solutions (at pH = 5.5) compared to solutions at normal, physiological pH. The rate of hydrolysis can be tuned to range from minutes to months through the addition of electron donating or withdrawing groups.&#x2028; The NEBI linker can be used to conjugate a cytotoxic agent to a carrier. Carriers for this DDS include molecules such as tumor specific antibodies, polymers/nanoparticles, peptides, and ligands, that can target cancer cells or accumulate around tumors. Cytotoxic agents include FDA approved small molecules and chemotherapeutics.&#x2028; Methods and Materials:&#x2028; The NEBI was developed into a bifunctional crosslinker containing a carboxylic acid and an azide for conjugation of cancer therapeutics to carriers. For simplicity, we used Human Serum Albumin (HSA) as our model carrier and doxorubicin as our model cytotoxic agent. The NEBI was conjugated to doxorubicin through a simple amide coupling. The NEBI was then conjugated to an alkyne containing HSA via “Click Chemistry.”&#x2028; Results:&#x2028; We were able to load approximately 1-2 doxorubicin molecules per HSA. Imaging studies have shown that our HSA conjugates to doxorubicin via a NEBI linker (HSA-NEBI-dox) localize in lysosomes. Cytotoxicity studies show HSA-NEBI-dox is cytotoxic while HSA conjugates to doxorubicin via a stable linkage is not.&#x2028; Discussion:&#x2028; We were able to develop methods for conjugating doxorubicin to HSA. The techniques used here can be applied to conjugate other carriers and other cancer therapeutics. We will continue to develop the NEBI linker and demonstrate how the linker can be used to conjugate trastuzumab to doxorubicin. We chose use trastuzumab, a monoclonal antibody, as a carrier because it is known to bind to the HER2 receptor. HER2 is over expressed in 25%-30% of breast cancers. Trastuzumab not only targets cancer cells that are over expressing the HER2 receptor, but binding of trastuzumab to the HER2 receptor can trigger receptor mediated endocytosis, which can lead to controlled release of doxorubicin within the cell.&#x2028; &#x2028;
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2156.
Novel thermal tumor ablation for breast cancer in mice using magnetic nanoparticles.
Authors: Motomura K , Ishitobi M , Komoike Y , Koyama H , Inaji H , Inoue M , Nagae H , Nagano I 
Published: December 2010

Abstract
Abstract #2158
Background: Thermal ablation therapy using lasers, ultrasound and microwaves is being investigated as a less invasive alternative to surgery for breast cancer. This study examined the efficacy of magnetic nanoparticles, which produce heat when exposed to an alternating magnetic field, for the destruction of breast cancer in mice.&#x2028; Material and Methods: Tumors were induced on both sides of the back of BALB/C mice by subcutaneous injection of MDA-MB-231 breast cancer cells. Magnetic nanoparticles were injected in and around one of the tumors in a mouse, while saline were injected in another tumor (control). Mice were exposed to an alternating magnetic field for 40 min. The temperature of the tumor injected with nanoparticles reached 45°C and was maintained at that temperature by adjusting the magnetic field intensity. Histopathological response was evaluated one to two months after thermal ablation therapy.&#x2028; Results: In 8 (67%) of 12 mice, complete tumor regression was observed in tumors treated with nanoparticle injection, while there was no regression in control tumors in any of the mice. There was no irreversible damage seen in normal tissue surrounding the nanoparticle injected tumors.&#x2028; Discussion: Since this procedure can destroy cancer cells specifically without injuring normal tissue, it may be applicable to the treatment of human breast cancer. Moreover, it may be possible to develop this procedure into a systemic therapy for tumor-specific targeting.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2158.
Micrometastases and isolated tumor cells: relevant and robust or rubbish? (MIRROR): preliminary results of the MIRROR study from the Dutch breast cancer trialists' group (BOOG).
Authors: de Boer M , van Deurzen CH , van Dijck JA , Borm GF , van Diest PJ , Adang EM , Nortier HW , Rutgers EJ , Seynaeve C , Menke-Pluymers MB , Bult P , Tjan-Heijnen VC 
Published: December 2010

Abstract
Abstract #23
Background&#x2028; The sentinel lymph node procedure (SNP) has largely replaced axillary lymph node dissection (ALND) in patients with early breast cancer (BC). Intensified examination of the sentinel node (SN) results in the detection of isolated tumor cells (ITCs) and micrometastases, whereas its relevance is still debated. This retrospective cohort study is the first study on this topic which includes only patients who underwent a SNP, with central review of all SN slides, and with separate analyses for the impact of administration of adjuvant systemic therapy.&#x2028; Methods&#x2028; Patients operated for BC in all Dutch hospitals in the years 1998-2005, having favourable tumor characteristics (&gt; 35 year; tumor size 1-3 cm and differentiation grade I-II OR tumor size ≤ 1 cm irrespective of grade), having undergone a SNP with pN0(i-), pN0(i+), or pN1mi as final N-stage were selected. Patients were classified in cohort I in case of pN0(i-) and no adjuvant systemic therapy (AST), in cohort II in case of pN0(i+)/pN1mi and no AST, and in cohort III in case of pN0(i+)/pN1mi with AST. SNs were centrally reviewed and restaged according to 6th TNM classification. The 5-year disease-free survival (DFS) was analysed for the 3 different cohorts.&#x2028; Results&#x2028; So far, data are available for 1,744 of the 3,240 selected patients (cohort I n=935; cohort II n=340, cohort III n=469) with a median follow-up of 5.5 years. At diagnosis median age was 58, 56 and 56 years (p &lt; 0.01) and median tumor size was 1.2, 1.4 and 1.5 cm (p &lt; 0.0001). Differentiation grade and hormone receptor status were equally distributed among the three cohorts. Adjuvant systemic therapy in cohort III consisted of chemotherapy (10%), hormonal therapy (63%), or both (27%). The 5-yr DFS is 84% in cohort I, 73% in cohort II, and 86% in cohort III (p = 0.003 cohort I vs II; p &lt; 0.0001 cohort II vs III). Correction for baseline characteristics did not lead to a relevant change in the results.&#x2028; Conclusion&#x2028; BC patients with ITCs or micrometastases as final N-stage after SNP have a significantly worse 5-yr DFS as compared to patients having no ITCs or micrometastases, independent of primary tumor characteristics. Adjuvant systemic therapy significantly improves the 5-yr DFS in the group of patients with ITCs or micrometastases in the lymph node(s). At the meeting, updated analyses will be available for the entire MIRROR study population.&#x2028; Support: The Netherlands organization for health research and development (ZonMw) and all Dutch CCCs.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 23.
Determination of HER2 amplification by in situ hybridization: when should chromosome 17 also be determined?.
Authors: Bartlett JM , Campbell FM , Mallon EA 
Published: December 2010

Abstract
Abstract #3002
Introduction: Aberrations of chromosome 17 (aneusomy) are common in breast cancer and therefore have a critical impact on the assessment and reporting of HER2 gene amplification in a significant sub-set of cases. There is an ongoing debate as to the proportion of cases for which assessment of chromosome 17 copy number may be important. According to current guidelines1,2, amplification of HER2 is considered to be a HER2/chromosome 17 ratio ≥2.0 and a ratio &lt;2.0 is regarded as non-amplified. For HER2 gene copy number assays, it has been assumed that copy numbers of &gt;6.0 reflect amplification and a result of &lt;4.0 HER2 gene copies per nucleus is always associated with lack of amplification; cases with 4-6 copies per cell are thought to require validation by testing of a parallel section for chromosome 171,2. To our knowledge, this assumption has not been verified experimentally.&#x2028; Methods: HER2 and chromosome 17 were measured by dual color FISH in 1711 breast cancer samples referred to the authors laboratories between 2000-2008. Using HER2 copy number and chromosome 17 data the impact of chromosome 17 testing upon accuracy of diagnosis of gene amplification was assessed.&#x2028; Results: At a HER2 copy number of 2 to &lt;3, 16 of 488 cases (3.3%) had HER2 amplification; and at a copy number of 3 to &lt;4, 32 of 195 cases (16.4%) were amplified. The proportion of cases with HER2 amplification increased considerably at HER2 copy numbers of 4 to &lt;7: 50.0% at 4 to &lt;5; 67.5% at 5 to &lt;6, and 77.3% at 6 to &lt;7. Virtually all cases were amplified at HER2 copy numbers of ≥7.&#x2028; Conclusion: Werecommend that all cases with observed HER2 copy numbers of 2 to 7 should also be analyzed for chromosome 17 in order to accurately determine HER2 gene amplification. This would require analysis of chromosome 17 in 48.3% of all breast cancer cases based upon the study population. Current guidelines1,2 recommend chromosome 17 measurement only in cases with a HER2 copy number of 4 to &lt;6, which represents only 6.6% of all breast cancer cases in the current study. Although single color ISH is becoming more widely used with the availability of CISH, the importance of chromosome 17 measurement cannot be ignored. It is essential that HER2 testing is of high quality, so that optimal patient management can be provided.&#x2028; 1. Ellis IO, Bartlett J, Dowsett M et al: Updated recommendations for HER2 testing in the UK. J.Clin.Path. 57(3), 233-237 (2004).&#x2028; 2. Wolff AC, Hammond ME, Schwartz JN et al: American Society of Clinical Oncology/College of American Pathologists Guideline Recommendations for Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer. Journal of Clinical Oncology 25(1), 118-145 (2007).
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3002.
Contribution of Mib1 to the SBR grade for prediction of metastatic recurrence in breast cancer.
Authors: MacGrogan G , deMascarel I , Debled M , Tunon de Lara C , Brouste V , Bonnefoi H , Mauriac L 
Published: December 2010

Abstract
Abstract #3003
Background: The Scarff Bloom and Richardson (SBR) histologic grade, which assesses tumor differentiation, nuclear pleomorphism and tumor proliferation through a mitotic score, is known to be an independent prognostic factor in breast cancer. Ki-67 is a nuclear protein that is expressed by cells that are engaged in the cell cycle and may be a more accurate proliferation marker than the mitotic score used in SBR grade. The aim of our study was to look at the prognostic value of ki-67 (detected with Mib1 antibody) in breast cancer and if it could improve the prognostic value of SBR grade (SBR G).&#x2028; Materials and Methods: We analyzed ki-67 expression by immunohistochemistry using the Mib1 antibody on tissue microarrays comprising four 0.6mm diameter tissue cores of 1033 consecutive invasive ductal carcinomas (290 SBR G1, 470 SBR G2, 273 SBR G3) operated on between 1989 and 1993 (median follow-up: 167 months, 280 metastatic events). Using the median and 75th percentile values of Mib1 expression in the series (10 % and 20%, respectively) as cut offs, we defined a three tiered Mib1 score and used it to replace the mitotic score in the SBR G (Mib1 G). The prognostic values of Mib1 score alone, SBR G, Mib1 G and combined SBR/Mib1 G using the higher of the 2 grades to assign tumors to a risk category were assed by univariate analysis using the Log-rank test with the Kaplan Meier method.&#x2028; Results: 53/290 (18%) and 53/470 (11%) of SBR G1 and 2 tumors were reclassified in combined SBR/Mib1 G2 and G3, respectively. In the combined SBR/Mib1 G three groups of tumors could be individualized according to their metastatic risk.&#x2028; &#x2028; Patients with SBR G1/Mib1 G1 tumors had the lowest metastatic risk. Patients with SBR G1/Mib1 G2 tumors, SBR G2/Mib1 G1 tumors and SBR G2/Mib1 G2 tumors had an intermediate risk. Finally, patients with SBR G2/Mib1 G3 tumors, SBR G3/Mib1 G2 and SBR G3/Mib1 G3 tumors had the highest metastatic risk. Mib1 score, Mib1 G, SBR G, and combined SBR/Mib1 G were all strongly associated with Metastasis-free Interval (p=3.10-10, p=8.10-11, p=2.10-12 and p=4.10-13, respectively).&#x2028; Discussion: In the combined grade patient assignment to risk category (low, intermediate or high) is made on the higher of the two grades. Metastatic risk was more accurately estimated when SBR and Mib1 grades were combined compared to SBR G or Mib1 G separately. Mib1 may complement the prognostic information provided by histologic grade.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3003.
Clinical significance of the entity 'flat epithelial atypia' on core needle biopsies of breast.
Authors: Dabbs DJ , Bhargava R , Tseng G , Chivukula M 
Published: December 2010

Abstract
Abstract #3006
Background: Flat epithelial atypia (FEA) is a newly emerging entity of uncertain clinical significance. Defined by the World Health Organization (WHO) in 2003, FEA differs from columnar cell hyperplasia by the presence of nuclear atypia and from atypical ductal hyperplasia (ADH) by the absence of complex architecture. As the term FEA is relatively new, the clinical relevance and the outcome data are sparse. The aim of this study is to evaluate the clinical and pathologic significance of this entity in order to construct the proper management of these lesions.&#x2028; Design: All core-needle biopsies (CNB) diagnosed as ADH, which includes pure FEA at our institution, from January 2006-April 2008 were retrieved from our pathology files. Hematoxylin and eosin (H&E) slides of five levels on each case were reviewed. Statistical analysis was performed with calculation of p-value.&#x2028; Results: Total number of CNB performed from 2006-2008 was 8054. 99% (8051/8054) were stereotactic guided and 1% (3/8054) were ultrasound/MRI guided biopsies. All the CNB were performed for microcalcifications. The mean age of the patients is 54 years (range 29-83). Incidence of ADH was 4% (338/8054). We have reviewed 203 cases so far and the study is ongoing. 32 cases were discarded due to either presence of DCIS or IC in the CNB. Upon review, 9% (18/203) cases were classified as pure FEA and 91% (185/203) cases as FEA+ADH. The upstaging to a significant lesion in pure FEA group is 14% in comparison to 12% in FEA+ADH group (p=0.9471), is not statistically significant. Lobular neoplasia is seen in association with pure FEA group in 33% (6/18) and 11% (21/185) in FEA+ADH group. In 6% (11/185) of cases in FEA+ADH group, we observed FEA evolved into ADH at the same site at an average of 3-4 levels.&#x2028; Conclusions: 1.The incidence of FEA in our CNB targeted for calcifications is 9% 2. The upstaging in the follow-up resections in FEA in comparison to ADH+FEA shows no statistical difference (14% versus 12%). 3. Since FEA and ADH commonly occur together on the same slide, it is prudent to examine deeper tissue levels when pure FEA is encountered on CNB.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3006.
Improved methods of detection, and prognostic significance, of vascular invasion in breast cancer.
Authors: Mohammed RA , Ellis IO , Green AR , Paish EC , Gill MS , Martin SG 
Published: December 2010

Abstract
Abstract #3010
Vascular invasion, encompassing both lymphovascular (LVI) and blood vascular invasion (BVI), influences breast cancer patient prognosis. We have previously shown, using an immunohistochemical approach to distinguish between LVI and BVI in a well characterized group of 177 consecutive paraffin-embedded specimens breast cancer patients (52 LN+ and 125 LN-), that VI was detected in 32% of specimens and that 96% of such VI were invasion of lymphatic vessels. The presence of LVI was significantly associated with the presence of metastasis, recurrence and worse disease free interval (DFI) and overall survival (OS). In multivariate analysis, LVI was an independent poor prognostic factor. This original study has been expanded by examining LVI, assessed by podoplanin staining, in 1000 LN-, early stage, breast cancers. In addition to verifying initial results showing the prognostic power of detection of LVI in early stage tumours, it also allowed an examination of LVI in histological and basal phenotypes to determine if the frequency of LVI influences prognosis in different breast cancer phenotypes.&#x2028; LVI was detected in 212 (21% of specimens). The lowest LVI positivity was observed in tubular carcinoma (5.6%), followed by mucinous (7.1%) and atypical medullary (18.5%) types. The highest LVI positivity was detected in invasive carcinoma of no special type (26%). Tumours with basal phenotype were significantly associated with higher LVI (29%) compared with 19% in non-basal tumours P =0.002.&#x2028; In the LVI-positive specimens; 203 (76%) specimens had peri-tumoural LVIs and 58 (24%) had an LVI in intra-tumoural vessels (9 specimens had LVIs in the intra-tumoural vessels only and 49 specimens had an LVI in both intra- and peri-tumoural vessels). The frequency of LVI ranged from 1 to 79: 167specimens (79%) had &lt;5 LVIs, 23 (11%) had 6-10 LVIs and 22 (10%) had &gt;10LVIs. There was no significant difference between the frequency of LVI and development of recurrence or death from the disease.&#x2028; Patients with LVI had a significantly worse prognosis. The 20-year OS rate was 85% in patients without LVI compared with 68% in patients with LVI. In multivariate analysis for OS, tumour size (P =0.004), tumour grade (P&lt; 0.0001), and LVI (P &lt;0.0001) retained significance. However, for DFI, only LVI (P&lt;0.0001) remained significant.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3010.
Are there preoperative predictors for invasive disease in DCIS?.
Authors: McArdle K , Shokuhi S , Chan Y , Vishwanath L , Brown H 
Published: December 2010

Abstract
Abstract #3014
Introduction: Ductal carcinoma in situ (DCIS) of the breast is defined as a proliferation of malignant epithelial cells within breast ducts without evidence of invasion through the basement membrane. Core needle biopsy (CNB) is used to sample both symptomatic and screen detected breast lesions preoperatively. However in a proportion of patients invasive disease is identified following surgical excision and as a result an upstaged patient may need to undergo additional surgery for axillary nodal evaluation such as sentinel lymph node biopsy (SLNB). Our aim was to evaluate predictive factors for invasive disease in this group.&#x2028; Method: Data from all patients with preoperative diagnosis of DCIS on core biopsy between February 2006 and December 2007 were analysed. Demographic data, screening /symptomatic presentation, palpability, size and histological features of DCIS on core biopsy including presence/absence of comedo necrosis, size of post operative invasion when present and result of axillary staging in this group was recorded. All patients with invasive disease had axillary staging.&#x2028; Results: A total of 75 patients were identified (all female), median age 63 (range 38-77). 72% (54/75) were screen detected. All palpable lesions were in the symptomatic group (13/19). Invasive disease was identified in 18 (24%) on post operative histology (2 micro-invasions). Only one patient with invasive disease had axillary involvement.&#x2028; &#x2028; Invasive disease was significantly higher in symptomatic and palpable lesions (P=0.04). Size of the lesion was significantly larger in the invasive group (P=0.04). High grade histology or presence of comedo necrosis was not a predictor of invasive disease in our series.&#x2028; Conclusion: A quarter of patients were upstaged and required axillary staging. 50% of symptomatic, palpable lesions larger than 20mm were found to be invasive on final histology, this group accounted for the only positive axilla. Symptomatic patients presenting with large, palpable areas of DCIS should be considered for axillary ultrasound scan and/or SLNB.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3014.
Akt-dependent phosphorylation on AIB1 serine 967 contributes to breast cancer tamoxifen resistance.
Authors: Shou J , Osborne KC , Gee J , Nicholson R , Schiff R 
Published: December 2010

Abstract
Abstract #3021
AIB1, a coactivator for nuclear receptors and other transcription factors, is involved in breast cancer development and progression. Overexpression of both AIB1 and HER2/neu (HER2) results in tamoxifen (Tam) resistance in clinical and experimental breast cancer. We hypothesized that HER2 signaling, via its downstream kinase Akt, leads to phosphorylation and activation of AIB1, which may then contribute to development of Tam resistance by reducing its antagonist activity.&#x2028; We have previously shown that Akt synergizes with AIB1 to enhance estrogen- and Tam-induced estrogen receptor (ER)-dependent transcriptional activity. This synergy is mainly mediated by Akt phosphorylation of AIB1 on serine 967, which is located between the nuclear receptor and the CBP/p300 interacting domains. We showed that this serine residue was phosphorylated specifically by Akt both in vitro and in vivo, including in both acquired and de novo Tam-resistant xenograft models that are associated with increased Akt signaling. More recent data showed that serine 967 of AIB1 is phosphorylated in Tam-resistant MCF7 tumors, and that this phosphorylation is stable in the resistant cells. By using immunoprecipitation and Western blot analysis, in ER positive breast tumors from patients, 90% of tumors were positive for total AIB, while AIB1 phosphorylation was detectable in 60% of tumors. Phosphorylated AIB1 was positively correlated with total and phosphorylated HER2 (Tyrosine 1248) (p=0.004 and p=0.0008 respectively, Fisher's exact test), implying that phophorylation of serine 967 of AIB1 may be stimulated by HER2 in these AIB1 positive tumors. Serine 967 of AIB1 was also phosphorylated in breast cancer cell lines, including both basal (HCC1954, BT20 and SUM190PT) and luminal (T47D, ZR7530, MDAMB361, and UACC812) subtypes, in which HER2 (except BT20) and Akt were activated .&#x2028; Taken together, Akt phosphorylation of AIB1 serine 967 appears important for AIB1 to function as an ER coactivator and regulator of breast cancer proliferation, and for Tam agonistic activity. Thus phosphorylation at serine 967 of AIB1 may be an essential factor required for Tam resistance as well as for tumor growth independent of ER. Additional regulatory roles of serine 967 in AIB1 function are currently under investigation.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3021.