Sarah L. Blair

Integrin α4β1 Signaling Is Required for Lymphangiogenesis and Tumor Metastasis

Recent studies have shown that lymphangiogenesis or the growth of lymphatic vessels at the periphery of tumors promotes tumor metastasis to lymph nodes. We show here that the fibronectin-binding integrin alpha4beta1 and its ligand fibronectin are novel functional markers of proliferative lymphatic endothelium. Tumors and lymphangiogenic growth factors, such as vascular endothelial growth factor-C (VEGF-C) and VEGF-A, induce lymphatic vessel expression of integrin alpha4beta1. Integrin alpha4beta1 then promotes growth factor and tumor-induced lymphangiogenesis, as genetic loss of integrin alpha4beta1 expression in Tie2Cre+ alpha4(loxp/loxp) mice or genetic loss of alpha4 signaling in alpha4Y991A knock-in mice blocks growth factor and tumor-induced lymphangiogenesis, as well as tumor metastasis to lymph nodes. In addition, antagonists of integrin alpha4beta1 suppress lymphangiogenesis and tumor metastasis. Our studies show that integrin alpha4beta1 and the signals it transduces regulate the adhesion, migration, invasion, and survival of proliferating lymphatic endothelial cells. As suppression of alpha4beta1 expression, signal transduction, or function in tumor lymphatic endothelium not only inhibits tumor lymphangiogenesis but also prevents metastatic disease, these results show that integrin alpha4beta1-mediated tumor lymphangiogenesis promotes metastasis and is a useful target for the suppression of metastatic disease.

Attaining Negative Margins in Breast-Conservation Operations: Is There a Consensus among Breast Surgeons?

BACKGROUND The purpose of this survey was to ascertain the most common surgical practices for attaining negative (tumor-free) surgical margins in patients desiring breast-conservation treatment for breast cancer to see if a consensus exists for optimal treatment of patients. STUDY DESIGN We sent a survey to 1,000 surgeons interested in the treatment of breast cancer. Three hundred eighty-one surgeons responded to this survey and 351 were used for the analysis (response rate of 38%). RESULTS Answers showed a large variety in clinical practices among breast surgeons across the country. There was little intraoperative margin analysis; only 48% of surgeons examine the margins grossly with a pathologist and even fewer used frozen sections or imprint cytology. Decisions to reexcise specific margins varied greatly. For example, 57% of surgeons would never reexcise for a positive deep margin, but 53% would always reexcise for a positive anterior margin. Most importantly, there was a large range in answers about acceptable margins with ductal carcinoma in situ and invasive carcinoma. Fifteen percent of surgeons would accept any negative margin, 28% would accept a 1-mm negative margin, 50% would accept a 2-mm negative margin, 12% would accept a 5-mm negative margin, and 3% would accept a 10-mm negative margin. CONCLUSIONS Results of this survey highlight the wide variety of practice patterns in the US for handling surgical margins in breast-conservation treatment. This issue remains controversial, with no prevailing standard of care. Consequently, additional study is needed in the modern era of multimodality treatment to examine the minimal amount of surgical treatment necessary, in conjunction with chemotherapy and radiation, to attain adequate local control rates in breast-conservation treatment.

Initial clinical experience with the Strut-Adjusted Volume Implant (SAVI) breast brachytherapy device for accelerated partial-breast irradiation (APBI): first 100 patients with more than 1 year of follow-up.

PURPOSE The Strut-Adjusted Volume Implant (SAVI; Cianna Medical, Aliso Viejo, CA) is a multichannel single-entry brachytherapy device designed to allow dose modulation to minimize normal tissue dose while simultaneously maximizing target coverage. This is the first report on the initial 102 patients with nearly 2 years of median follow-up. METHODS AND MATERIALS One hundred two patients were treated at two institutions. Data were collected on eligibility and dosimetry and followed for toxicity and recurrence. RESULTS The median follow-up is 21 months. Overall dosimetry is outstanding (median percent of target volume receiving 90% of the prescription dose was 95.9%, volume of target receiving 150% of the prescription dose was 27.8 mL, and volume of target receiving 200% of the prescription dose was 14.0 cm(3)). No devices were pulled prior to treatment completion. For patients with a skin bridge of less than 7 mm, the maximum median skin dose was 280 cGy (median percent of target volume receiving 90% of the prescription dose was 95.2%, volume of target receiving 150% of the prescription dose was 25.8 cm(3) and volume of target receiving 200% of the prescription dose was 12.7 mL). For patients with both chest wall and skin of less than 7 mm, the maximum median lung dose was 205 cGy with simultaneous skin dose of 272 cGy. The rate of telangiectasia was 1.9%. Grade 1 hyperpigmentation developed in 10 patients (9.8%) and Grade 2 fibrosis in 2 patients (1.9%). There were 2 symptomatic seromas and 2 cases of asymptomatic fat necrosis (1.9%). Of the patients, 27% were not eligible for MammoSite balloon brachytherapy (Hologic, Inc., Marlborough, MA) and 5% were not eligible for any balloon brachytherapy. The recurrence rate was 1%. CONCLUSIONS The SAVI appears to safely allow an increase in eligibility for APBI over balloon brachytherapy or three-dimensional conformal radiation, highlighting the outstanding device flexibility to maximize the target dose and minimize the normal tissue dose. The device was well tolerated by patients.

Hollow silica and silica-boron nano/microparticles for contrast-enhanced ultrasound to detect small tumors

Diagnosing tumors at an early stage when they are easily curable and may not require systemic chemotherapy remains a challenge to clinicians. In order to improve early cancer detection, gas filled hollow boron-doped silica particles have been developed, which can be used for ultrasound-guided breast conservation therapy. The particles are synthesized using a polystyrene template and subsequently calcinated to create hollow, rigid nanoporous microspheres. The microshells are filled with perfluoropentane vapor. Studies were performed in phantoms to optimize particle concentration, injection dose, and the ultrasound settings such as pulse frequency and mechanical index. In vitro studies have shown that these particles can be continuously imaged by US up to 48 min and their signal lifetime persisted for 5 days. These particles could potentially be given by intravenous injection and, in conjunction with contrast-enhanced ultrasound, be utilized as a screening tool to detect smaller breast cancers before they are detectible by traditional mammography.

Oncologic Safety of Skin-Sparing and Nipple-Sparing Mastectomy: A Discussion and Review of the Literature

Breast conservation therapy has been the cornerstone of the surgical treatment of breast cancer for the last 20 years; however, recently, the use of mastectomy has been increasing. Mastectomy is one of the most frequently performed breast operations, and with novel surgical techniques, preservation of the skin envelope and/or the nipple-areolar complex is commonly performed. The goal of this paper is to review the literature on skin-sparing mastectomy and nipple-sparing mastectomy and to evaluate the oncologic safety of these techniques. In addition, this paper will discuss the oncologic importance of margin status and type of mastectomy as it pertains to risk of local recurrence and relative need for adjuvant therapy.

Initial clinical experience with the Strut-Adjusted Volume Implant brachytherapy applicator for accelerated partial breast irradiation

PURPOSE Accelerated partial breast irradiation is becoming increasingly popular. The Cianna single-entry high-dose-rate applicator, Strut-Adjusted Volume Implant (SAVI, Cianna Medical, Aliso Viejo, CA), contains peripheral struts allowing greater planning flexibility for small-breasted women, technically easier insertion, and normal tissue exposure minimization. This study evaluates early clinical experience. METHODS AND MATERIALS Thirty patients treated with the SAVI with a median followup of 12 months were evaluated. The median age was 59.5. Tumor size averaged 0.9cm. Fifteen cancers were ductal carcinoma in situ (50%), 1 was invasive lobular (3.3%), 4 were tubular (6.7%), and the rest infiltrating ductal (40%). Most of them were estrogen receptor (ER) positive (90%). Nine women (30%) were premenopausal. RESULTS Dosimetry was outstanding with median V90, V150, and V200 of 96.2%, 24.8, and 12.8cc. There were no symptomatic seromas, and one report of asymptomatic fat necrosis seen on mammogram at 1 year. In patients who had skin spacing of less than 1cm, the median skin dose was 245cGy/fraction. The median rib and lung dose per fraction for those patients with either structure less than 1cm was 340 and 255cGy (75% of prescribed dose), respectively. There have been no local recurrences to date. CONCLUSIONS Early clinical experience with the SAVI demonstrates the ease of placement of a single-entry brachytherapy device combined with the increased dose modulation of interstitial brachytherapy. Dose to normal structures has remained exceedingly low. Almost half of evaluated patients were not candidates for other single-entry brachytherapy devices because of skin spacing or breast size, demonstrating an expansion of candidates for single-entry partial breast brachytherapy.

Early cancer detection among rural and urban californians

BackgroundSince the stage of cancer detection generally predicts future mortality rates, a key cancer control strategy is to increase the proportion of cancers found in the early stage. This study compared stage of detection for members of rural and urban communities to determine whether disparities were present.MethodsThe California Cancer Registry (CCR), a total population based cancer registry, was used to examine the proportion of early stage presentation for patients with breast, melanoma, and colon cancer from 1988 to 2003. Cancer stage at time of detection for these cancers was compared for rural and urban areas.ResultsIn patients with breast cancer, there were significantly more patients presenting at early stage in 2003 compared to 1988, but no difference in the percentage of patients presenting with early stage disease between rural and urban dwellers. There were no differences in incidence in early stage cancer incidence between these groups for melanoma patients, as well. In colorectal cancer in 1988, significantly more patients presented with early stage disease in the urban areas (42% vs 34%, p < 0.02). However, over time the rural patients were diagnosed with early stage disease with the same frequency in 2003 as 1988.ConclusionThis analysis demonstrates that people in rural and urban areas have their breast, melanoma or colorectal cancers diagnosed at similar stages. Health care administrators may take this information into account in future strategic planning.

Color Doppler Ultrasound and Gamma Imaging of Intratumorally Injected 500 nm Iron–Silica Nanoshells

Perfluoropentane gas filled iron-silica nanoshells have been developed as stationary ultrasound contrast agents for marking tumors to guide surgical resection. It is critical to establish their long-term imaging efficacy, as well as biodistribution. This work shows that 500 nm Fe-SiO2 nanoshells can be imaged by color Doppler ultrasound over the course of 10 days in Py8119 tumor bearing mice. The 500 nm nonbiodegradable SiO2 and biodegradable Fe-SiO2 nanoshells were functionalized with diethylenetriamine pentaacetic acid (DTPA) ligand and radiolabeled with (111)In(3+) for biodistribution studies in nu/nu mice. The majority of radioactivity was detected in the liver and kidneys following intravenous (IV) administration of nanoshells to healthy animals. By contrast, after nanoshells were injected intratumorally, most of the radioactivity remained at the injection site; however, some nanoshells escaped into circulation and were distributed similarly as those given intravenously. For intratumoral delivery of nanoshells and IV delivery to healthy animals, little difference was seen between the biodistribution of SiO2 and biodegradable Fe-SiO2 nanoshells. However, when nanoshells were administered IV to tumor bearing mice, a significant increase was observed in liver accumulation of SiO2 nanoshells relative to biodegradable Fe-SiO2 nanoshells. Both SiO2 and Fe-SiO2 nanoshells accumulate passively in proportion to tumor mass, during intravenous delivery of nanoshells. This is the first report of the biodistribution following intratumoral injection of any biodegradable silica particle, as well as the first report demonstrating the utility of DTPA-(111)In labeling for studying silica nanoparticle biodistributions.

Adenoid Cystic Breast Carcinoma: Is Axillary Staging Necessary in All Cases? Results from the California Cancer Registry

Abstract:  Adenoid cystic carcinoma (ACC) is an uncommon type of breast cancer. There are limited data about its epidemiology, tumor characteristics, and outcomes. Using a large, population‐based data base, this study aimed to identify specific characteristics of patients with adenoid cystic breast cancer, investigate its natural history, and determine its long‐term prognosis. The California Cancer Registry, a population‐based registry, was reviewed from the years 1988 to 2006. The data were analyzed with relation to patient age, tumor size and stage, and overall survival. Relative cumulative actuarial survival was determined using the Berkson‐Gage life table method. A total of 244 cases of invasive adenoid cystic cancer were identified in women during this time period. The patients’ median age was 61.9 years. Most cases were diagnosed in non‐Hispanic White women (82%, n = 200), followed by African American (6%, n = 15), Asian/Pacific‐Islander (5.7%, n = 14) and Hispanic women (4.4%, n = 12). The remainder of the patients was of unknown or other ethnicity. Tumors were between 1 and 140 mm in size. At the time of diagnosis, 92% (n = 225) of patients had localized disease, 5% (n = 12) of patients had regional disease, and even fewer (n = 7) had either distant or unknown staged disease. Lymph node involvement was not present in any tumors smaller than 1.4 cm. The relative cumulative survival of patients with adenoid cystic breast carcinoma was 95.6% at 5 years and 94.9% at 10 years. ACC of the breast is a rare disease with an overall good prognosis. Knowing that this cancer usually presents as localized disease, with lymph node involvement seen only with larger tumors, can help clinicians plan the operative management of these tumors.

Racial/Ethnic Differences in Early Detection of Breast Cancer: A Study of 250,985 Cases from the California Cancer Registry

AIMS This study analyzed early breast cancer detection rates as a surrogate for breast cancer mortality rates. Stage at diagnosis was broken down by race/ethnicity and year of diagnosis for the cases of female breast cancer in the California Cancer Registry from 1988 to 2002. METHODS A quarter million cases of breast cancer in women > or =50 years of age recorded in the California Cancer Registry over the period 1988-2002 were classified as early (in situ and localized stages) or late (regional and distant stages). The increases in the percent of cases that were early were studied by 3-year periods over this interval. In addition to the total group, data were broken down by race/ethnicity. The 3-year periods were used to compensate for small numbers of cases in some of the nonwhite groups. RESULTS The proportion of early stage female breast cancers reached a plateau at 70% in the mid-1990s. African American and Hispanic womens screening rates reached a plateau at a considerably lower rate. Only Pacific Islander/Asian American women demonstrated a sustained rise in the percent of early breast cancers detected through 2002, eventually nearing the rate of early detection set by white women. CONCLUSIONS The plateaus observed suggest that focused interventions continue to be needed for all women, especially for African American and Hispanic women if the American Cancer Societys 2015 goals are to be achieved.