[Show abstract][Hide abstract] ABSTRACT: Perfluoropentane (PFP) gas-filled biodegradable iron-doped silica nanoshells have been demonstrated as long-lived ultrasound contrast agents. Nanoshells are synthesized by a sol–gel process with tetramethyl orthosilicate (TMOS) and iron ethoxide. Substituting a fraction of the TMOS with R-substituted-trialkoxysilanes produces ultrathin nanoshells with varying shell thicknesses and morphologies composed of fused nanoflakes. The ultrathin nanoshells have continuous ultrasound Doppler imaging lifetimes exceeding 3 h, are twice as bright using contrast-specific imaging, and have decreased pressure thresholds compared to control nanoshells synthesized with just TMOS. Transmission electron microscopy shows that the R-group-substituted trialkoxysilanes can reduce the mechanically critical nanoshell layer to 1.4 nm. These ultrathin nanoshells have the mechanical behavior of weakly linked nanoflakes but the chemical stability of silica. The synthesis can be adapted for general fabrication of 3D nanostructures composed of nanoflakes, which have thicknesses from 1.4 to 3.8 nm and diameters from 2 to 23 nm.
[Show abstract][Hide abstract] ABSTRACT: Patients with human epidermal growth factor receptor 2 (HER2neu)-positive breast invasive cancer are known to have larger, more aggressive tumors. Little research exists on the relationship between HER2neu status and extent of ductal carcinoma In Situ (DCIS). A retrospective review of a single-institution database was performed for patients with DCIS between the years 2002 and 2011. A single blinded breast radiologist reviewed preoperative imaging. Pathology was reviewed for extent of DCIS. Primary outcome was mastectomy. Multivariate logistic regression was used to determine adjusted mastectomy risk. There were 166 cases, 34 HER2neu-positive. HER2neu receptor-positive patients had larger lesions on imaging: 4.0 versus 2.7 cm, by 2.9 versus 1.5 cm (P = 0.0499 and 0.0182). HER2neu-positive patients with DCIS were more likely than HER2neu-negative to undergo mastectomy than lumpectomy (53 vs 28%, P = 0.006). Pathology revealed a trend toward larger lesions in HER2neu-positive patients (2.96 vs 2.22 cm, nonsignificant). Patients with HER2neu-positive disease were three times more likely to undergo mastectomy (odds ratio, 2.9; 95% confidence interval, 1.23 to 6.78). Patients with HER2neu-positive DCIS had greater extent of disease by imaging and were more likely to undergo mastectomy than HER2neu-negative. These findings will help surgeons counsel patients on surgical treatment.
The American surgeon 10/2014; 80(10). DOI:10.1016/j.jss.2013.11.177 · 0.82 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Gender disparity in the Program Director role has not been studied. The goal of this study is to evaluate the percentage of women in Chair and Program Director positions. We hypothesize there is a higher percentage of women in the Program Director than Chair role.
An internet search identified Chairs, Program Directors, Associate Program Directors and Division Chiefs. Statistical analysis compared percentages of women in these roles at all institutions, academic/community programs, and region.
There is higher female representation in the Program Director than Chair position (P=.002) in General Surgery, otolaryngology, and orthopedics. More women are Associate Program Directors than Division Chiefs (23.6% vs9.8%, p=<.001). Academic and community programs are no different. In the West a greater percentage of women are Chairs as compared to the other regions (P<= .002).
There are higher rates of women in Program Director than Department Chair positions. This discrepancy warrants further investigation.
The American Journal of Surgery 09/2014; 208(3). DOI:10.1016/j.amjsurg.2013.11.005 · 2.29 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Oncolytic viruses (OVs) constitute a promising class of cancer therapeutics which exploit validated genetic pathways known to be deregulated in many cancers. To overcome an immune response and to enhance its potential use to treat primary and metastatic tumors, a method for liposomal encapsulation of adenovirus has been developed. The encapsulation of adenovirus in non-toxic anionic lecithin-cholesterol-PEG liposomes ranging from 140 to 180 nm in diameter have been prepared by self-assembly around the viral capsid. The encapsulated viruses retain their ability to infect cancer cells. Furthermore, an immunoprecipitation (IP) technique has shown to be a fast and effective method to extract non-encapsulated viruses and homogenize the liposomes remaining in solution. 78% of adenovirus plaque forming units were encapsulated and retained infectivity after IP processing. Additionally, encapsulated viruses have shown enhanced transfection efficiency up to 4× higher compared to non-encapsulated Ads. Extracting non-encapsulated viruses from solution may prevent an adverse in vivo immune response and may enhance treatment for multiple administrations.
[Show abstract][Hide abstract] ABSTRACT: Introduction:
Calcifications can be indicative of malignancy, but calcifications also can be a byproduct of necrotic tissue as cancer cells die. Current treatment regimens require excision of calcifications. The objective of this study was to examine the correlation between the extent of calcification on mammography and actual tumor size after neoadjuvant chemotherapy (NAC) as well as magnetic resonance imaging (MRI) for comparison.
We retrospectively reviewed all patients at the University of California, San Diego, who underwent NAC for breast cancer between 2007 and 2013. Pearson correlation coefficients were computed between breast imaging and pathological measurements.
There were 136 patients total. Average age was 51 years. Fifty-three patients had calcifications on imaging (calc+); 83 did not (calc-). In the calc- group, extent of disease measured by mammogram (MMG) and MRI correlated moderately well with pathological tumor size (0.46 and 0.48, p = not significant). In the calc+ group, MRI was more likely to correlate with pathology than MMG (0.55 vs. -0.12, p = 0.01). Twenty-five calc+ patients had increased calcification after NAC; six of these had complete pathologic response. MRI correlated better with tumor size on pathology in patients with anti-HER2neu-based regimens than in patients with cytotoxic chemotherapy-alone regimens (0.88 vs. 0.4, p = 0.0001). MRI also is more accurate at predicting pathological tumor size in patients with triple negative disease (p = 0.002).
Magnetic resonance imaging correlated well while MMG calcification measurements correlated poorly with tumor size on final pathology. Extent of calcifications on diagnostic mammography may not be accurate in preoperative evaluation of breast cancers after NAC.
[Show abstract][Hide abstract] ABSTRACT: Background:
High intensity-focused ultrasound (HIFU) is an alterative ablative technique currently being investigated for local treatment of breast cancer and fibroadenomas. Current HIFU therapies require concurrent magnetic resonance imaging monitoring. Biodegradable 500 nm perfluoropentane-filled iron-silica nanoshells have been synthesized as a sensitizing agent for HIFU therapies, which aid both mechanical and thermal ablation of tissues. In low duty cycle high-intensity applications, rapid tissue damage occurs from mechanical rather than thermal effects, which can be monitored closely by ultrasound obviating the need for concurrent magnetic resonance imaging.
Materials and methods:
Iron-silica nanoshells were synthesized by a sol-gel method on polystyrene templates and calcined to yield hollow nanoshells. The nanoshells were filled with perfluoropentane and injected directly into excised human breast tumor, and intravenously (IV) into healthy rabbits and Py8119 tumor-bearing athymic nude mice. HIFU was applied at 1.1 MHz and 3.5 MPa at a 2% duty cycle to achieve mechanical ablation.
Ex vivo in excised rabbit livers, the time to visually observable damage with HIFU was 20 s without nanoshells and only 2 s with nanoshells administered IV before sacrifice. Nanoshells administered IV into nude mice with xenograft tumors were activated in vivo by HIFU 24 h after administration. In this xenograft model, applied HIFU resulted in a 13.6 ± 6.1 mm(3) bubble cloud with the IV injected particles and no bubble cloud without particles.
Iron-silica nanoshells can reduce the power and time to perform HIFU ablative therapy and can be monitored by ultrasound during low duty cycle operation.
Journal of Surgical Research 05/2014; 190(2). DOI:10.1016/j.jss.2014.05.009 · 1.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Randomized trials have clearly established breast conservation therapy (BCT) as appropriate treatment for early-stage invasive breast cancer. Current evidence shows that positive margins confer a greater than twofold risk of ipsilateral breast tumor recurrence. Thus, patients who have positive margins after BCT warrant re-excision. With regard to negative margins, however, the optimal negative margin width remains unclear. This article reviews the recent guidelines set forth by the Society of Surgical Oncology and the American Society of Radiation Oncology regarding the margin width in stage I and II invasive breast cancer. We also discuss the controversies related to implementation of these guidelines.
Current Breast Cancer Reports 03/2014; 7(1):48-52. DOI:10.1007/s12609-014-0170-z
[Show abstract][Hide abstract] ABSTRACT: Breast reconstruction after mastectomy positively affects psychosocial well-being; however, the influence of reconstruction on cancer outcomes is unknown. The objective of our study was to compare survival in reconstructed versus nonreconstructed patients after mastectomy. All consecutive female patients diagnosed with invasive breast cancer and treated with mastectomy between 2002 and 2011 were identified from our single-institution database. All cancer operations were performed by two surgeons. Survival was calculated using the Kaplan-Meier method and compared using the log-rank test. To identify the effect of reconstruction on survival, a multivariate Cox regression analysis was performed. Of 474 patients treated, 340 (71.7%) underwent breast reconstruction. At a mean follow-up 3.3 years, reconstructed patients had a longer 5-year survival (91 vs 74%, P < 0.001). After controlling for age, race, payer source, cancer stage, triple negative status, and receipt of radiation or chemotherapy, reconstructed patients maintained a survival advantage over nonreconstructed patients (hazard ratio, 0.47; 95% confidence interval, 0.25 to 0.88; P = 0.02). Patients with breast cancer who undergo reconstruction have longer survival than nonreconstructed patients. The explanation for this finding may be related to improved psychosocial qualities of life versus possible antitumorigenic effects of implants.
The American surgeon 10/2013; 79(10):977-81. · 0.82 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Patients older than 80 years represent a significant breast cancer population but are underrepresented in clinical trials. It is established that estrogen receptor (ER)/progesterone receptor (PR)-negative status confers a worse prognosis in patients under 70, but this is not well studied in those over 80. We examined the prognosis of patients over 80 with ER/PR-negative disease to determine whether these patients are more likely to die of breast cancer than cardiovascular disease and to study treatment patterns.
We queried the Surveillance Epidemiology and End Results (SEER) database between 1992 and 2009 for patients with invasive breast carcinoma. Primary outcomes were breast cancer or cardiovascular death; secondary outcomes were radiotherapy and surgery. Cox proportional hazard analysis and logistic regression were used to determine adjusted outcomes over time. Subset analysis was performed comparing mortality rates by stage.
There were 502,807 patients, 6,933 over 80 with ER/PR-negative disease. ER/PR-negative patients over 80 faced decreased 10-year survival compared to ER/PR-positive patients (61.5, 81.4 %; p < 0.05). ER/PR-negative patients were more likely to die of breast cancer than of cardiovascular disease (25.6, 12.2 %). Adjusting for confounders, ER/PR-negative patients over 80 were more likely to die from breast cancer specifically than patients aged 50-79 years [hazards ratio (HR) 1.53, 95 % confidence interval (CI) 1.43-1.64]. This finding was consistent across all stages. Compared to younger cohorts, elderly patients with ER/PR-negative disease received less radiotherapy [odds ratio (OR) 0.42, 95 % CI 0.39-0.46] and had a trend for less surgery (OR 0.86, 95 % CI 0.69-1.07).
Elderly ER/PR-negative patients are more likely to die of their breast disease than cardiovascular disease. Standard treatment regimens, especially radiotherapy, should be considered for elderly patients.
[Show abstract][Hide abstract] ABSTRACT: 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 non-biodegradable 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-111In labeling for studying silica nanoparticle biodistributions.
[Show abstract][Hide abstract] ABSTRACT: Lymph nodes are initial sites of tumor metastasis, yet whether the lymph node microenvironment actively promotes tumor metastasis remains unknown. We show here that VEGF-C/PI3Kα-driven remodeling of lymph nodes promotes tumor metastasis by activating integrin α4β1 on lymph node lymphatic endothelium. Activated integrin α4β1 promotes expansion of the lymphatic endothelium in lymph nodes and serves as an adhesive ligand that captures vascular cell adhesion molecule 1 (VCAM-1)(+) metastatic tumor cells, thereby promoting lymph node metastasis. Experimental induction of α4β1 expression in lymph nodes is sufficient to promote tumor cell adhesion to lymphatic endothelium and lymph node metastasis in vivo, whereas genetic or pharmacological blockade of integrin α4β1 or VCAM-1 inhibits it. As lymph node metastases accurately predict poor disease outcome, and integrin α4β1 is a biomarker of lymphatic endothelium in tumor-draining lymph nodes from animals and patients, these results indicate that targeting integrin α4β1 or VCAM to inhibit the interactions of tumor cells with the lymph node microenvironment may be an effective strategy to suppress tumor metastasis.
Proceedings of the National Academy of Sciences 05/2013; 110(22). DOI:10.1073/pnas.1219603110 · 9.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background. Negative margins are associated with a reduced risk of ipsilateral breast tumor recurrence (IBTR) in women with early stage breast cancer treated with breast conserving surgery (BCS). Not infrequently, atypical ductal hyperplasia (ADH) is reported as involving the margin of a BCS specimen, and there is no consensus among surgeons or pathologists on how to approach this diagnosis resulting in varied reexcision practices among breast surgeons. The purpose of this paper is to establish a reasonable approach to guide the treatment of ADH involving the margin after BCS for early stage breast cancer. Methods. the published literature was reviewed using the PubMed site from the US National Library of Medicine. Conclusions. ADH at the margin of a BCS specimen performed for early stage breast cancer is a controversial pathological diagnosis subject to large interobserver variability. There is not enough data evaluating this diagnosis to change current practice patterns; however, it is reasonable to consider reexcision for ADH involving a surgical margin, especially if it coexists with low grade DCIS. Further studies with longer followup and closer attention to ADH at the margin are needed to formulate treatment guidelines.
International Journal of Surgical Oncology 12/2012; 2012:297832. DOI:10.1155/2012/297832
[Show abstract][Hide abstract] ABSTRACT: PURPOSE
We developed stable hollow monodispersed silica spheres as novel ultrasound (US) contrast agents that can be of any desired size, can be functionalized, and PEGylated to increase blood half life. The particles can also be injected in breast tumors for US guided tumor resection in lieu of the currently used radioactive beads. We report here the particle’s acoustic behavior in vitro and in vivo.
METHOD AND MATERIALS
we coated monodispersed 0.5 or 2 µm polystyrene beads with silica and removed the polystyrene core by calcination. Scanning and transmission electron microscopy showed monodispersed thin hallow spheres that were either 0.5 or 2µm in size. The naturally porous silica hollow shells were then filled with perfluoropentane vapor and suspended in an aqueous solution for injection. Various doses (10-200µL) of the 2 µm silica shells were injected in chicken breasts ex vivo and in rabbit breast tissues in vivo to assess signal longevity. Color and Power Doppler imaging were performed with a Siemens Sequoia 512 scanner over days. We imaged the 0.5µm shells in suspension and assessed the effect of MI on the US signal. We imaged normal rats and tumor-bearing mice after either intravenous (IV) or intraperitoneal (IP) injection using color/power Doppler and contrast specific modes.
The 2 µm shells were easily visible on Color/Power Doppler in tissues at the injection site that persisted up to 5 days after injection. The signal in rabbit breast tissue did not migrate from the injection site and lymph nodes did not enhance indicating stable labeling. As would be expected the 0.5µm shells produced no signal at very low MI and the signal increased as the MI increased thereafter. Following IV or IP injection, contrast enhancement was observed in the liver and tumors.
The hollow 2µm silica spheres stably mark the injection site for days and can be used to mark tumors for US guided surgical resection. The stable 0.5 µm shells can be given IV or IP to image perfused tissues and tumors with Doppler and Contrast specific imaging modes.
These particles may be used as stationary ultrasound markers or circulating ultrasound contrast agents.
Radiological Society of North America 2012 Scientific Assembly and Annual Meeting; 11/2012
[Show abstract][Hide abstract] ABSTRACT: Background. Breast conservation therapy (BCT) is the standard treatment for breast cancer; however, 32-63% of procedures have a positive margin leading to secondary procedures. The standard of care to evaluate surgical margins is based on permanent section. Imprint cytology (IC) has been used to evaluate surgical samples but is limited by excessive cauterization thus requiring experienced cytopathologist for interpretation. An automated image screening process has been developed to detect cancerous cells from IC on cauterized margins. Methods. IC was prospectively performed on margins during lumpectomy operations for breast cancer in addition to permanent section on 127 patients. An 8-slide training subset and 8-slide testing subset were culled. H&E IC automated analysis, based on linear discriminant analysis, was compared to manual pathologist interpretation. Results. The most important descriptors, from highest to lowest performance, are nucleus color (23%), cytoplasm color (15%), shape (12%), grey intensity (9%), and local area (5%). There was 100% agreement between automated and manual interpretation of IC slides. Conclusion. Although limited by IC sampling variability, an automated system for accurate IC cancer cell identification system is demonstrated, with high correlation to manual analysis, even in the face of cauterization effects which supplement permanent section analysis.
[Show abstract][Hide abstract] ABSTRACT: 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.
International Journal of Surgical Oncology 07/2012; 2012(6):921821. DOI:10.1155/2012/921821