Analysis of Surgical Trends for Axillary Lymph Node Management in Patients with Ductal Carcinoma In Situ Using the NSQIP Database: Are We Following National Guidelines?

BACKGROUND: For patients with ductal carcinoma in situ (DCIS), multiple national cancer organizations recommend that sentinel lymph node biopsy (SLNB) be offered when treated with mastectomy, but not when treated with breast-conserving surgery (BCS). This study analyzes national surgical trends of SLNB and axillary lymph node dissection (ALND) in DCIS patients undergoing breast surgery with the aim to quantify deviations from national guidelines. METHODS: A retrospective cohort analysis of the American College of Surgeons' National Surgical Quality Improvement Program (ACS NSQIP) database from 2005 to 2017 identified patients with DCIS. Patients were categorized by their primary method of breast surgery, i.e. mastectomy or BCS, then further categorized by their axillary lymph node (ALN) management, i.e. no intervention, SLNB, or ALND. Data analysis was conducted via linear regression and a non-parametric Mann-Kendall test to assess a temporal trend and Sen's slope. RESULTS: Overall, 43,448 patients with DCIS met the inclusion criteria: 20,504 underwent mastectomy and 22,944 underwent BCS. Analysis of DCIS patients from 2005 to 2017 revealed that ALND decreased and SLNB increased in every subgroup, regardless of surgical treatment modality. Evaluation in the mastectomy group increased overall: mastectomy alone increased from 57.1 to 65.8% (p < 0.01) and mastectomy with immediate reconstruction increased from 58.5 to 72.1% (p < 0.01). Increases also occurred in the total BCS population: partial mastectomy increased from 14.0 to 21.1% and oncoplastic surgery increased from 10.5 to 23.0% (both p < 0.01). CONCLUSIONS: Despite national guideline recommendations for the management of ALN surgery in DCIS patients, approximately 20-30% of cases continue to not follow these guidelines. This warrants further education for surgeons and patients.

Poor Access to Breast Reconstruction: A Geographical Shortage of Plastic Surgeons Relative to Breast Surgeons in the United States.

BACKGROUND: Breast cancer surgery involves removal of cancer performed by a breast surgeon and reconstruction performed by a plastic surgeon. Historically, many women have not undergone breast reconstruction surgery (BRS), with current literature suggesting that geographic barriers may play a role. Our objective was to determine if there is a geographic shortage of plastic surgeons in the United States and to assess for trends in access to BRS for rural, suburban, and urban populations. METHODS: A database investigation of the 2018 membership for the American Society of Breast Surgeons and the American Society of Plastic Surgeons was performed. We searched for a breast surgeon's geographic presence by zip code and looked for the presence of a plastic surgeon within 10 and 20 miles. Zip codes were then categorized as urban, suburban, or rural. Within each population category, the average numbers of breast surgeons and plastic surgeons were quantified. RESULTS: Twenty-five percent of breast surgeon zip codes had no plastic surgeons located within 10 miles; 10% of breast surgeon zip codes had no plastic surgeon within 20 miles. There were on average 7.03 breast surgeons in each urbanized area. Suburban and rural areas had an average of 1.14 and 1.00 breast surgeons, respectively. There were on average 10.97 plastic surgeons per urbanized area. Suburban and rural areas had, on average, 0.23 and 0.06 plastic surgeons, respectively. CONCLUSIONS: A national comparison of the geographical distribution between breast surgeons and plastic surgeons indicates a shortage of plastic surgeons, especially in rural and suburban areas.

Optical Mammography in Patients with Breast Cancer Undergoing Neoadjuvant Chemotherapy: Individual Clinical Response Index.

RATIONALE AND OBJECTIVES: We present an optical mammography study that aims to develop quantitative measures of pathologic response to neoadjuvant chemotherapy (NAC) in patients with breast cancer. Such quantitative measures are based on the concentrations of oxyhemoglobin ([HbO2]), deoxyhemoglobin ([Hb]), total hemoglobin ([HbT]), and hemoglobin saturation (SO2) in breast tissue at the tumor location and at sequential time points during chemotherapy. MATERIALS AND METHODS: Continuous-wave, spectrally resolved optical mammography was performed in transmission and parallel-plate geometry on 10 patients before treatment initiation and at each NAC administration (mean number of optical mammography sessions: 12, range: 7-18). Data on two patients were discarded for technical reasons. The patients were categorized as responders (R, >50% decrease in tumor size), or nonresponders (NR, <50% decrease in tumor size) based on imaging and histopathology results. RESULTS: At 50% completion of the NAC regimen (therapy midpoint), R (6/8) demonstrated significant decreases in SO2 (-27% ± 4%) and [HbT] (-35 ± 4 µM) at the tumor location with respect to baseline values. By contrast, NR (2/8) showed nonsignificant changes in SO2 and [HbT] at therapy midpoint. We introduce a cumulative response index as a quantitative measure of the individual patient's response to therapy. At therapy midpoint, the SO2-based cumulative response index had a sensitivity of 100% and a specificity of 100% for the identification of R. CONCLUSIONS: These results show that optical mammography is a promising tool to assess individual response to NAC at therapy midpoint to guide further decision making for neoadjuvant therapy.

Optical mammography: bilateral breast symmetry in hemoglobin saturation maps.

We present a study of the bilateral symmetry of human breast hemoglobin saturation maps measured with a broadband optical mammography instrument. We have imaged 21 patients with unilateral breast cancer, 32 patients with unilateral benign lesions, and 27 healthy patients. An image registration process was applied to the bilateral hemoglobin saturation (SO 2 SO2 ) images by assigning each pixel to the low, middle, or high range of SO 2 SO2 values, where the thresholds for the categories were the 15th and 85th percentiles of the individual saturation range. The Dice coefficient, which is a measure of similarity, was calculated for each patient's pair of right and left breast SO 2 SO2 images. The invasive cancer patients were found to have an average Dice coefficient value of 0.55±0.07 0.55±0.07 , which was significantly lower than the benign and healthy groups (0.61±0.11 0.61±0.11 and 0.62±0.12 0.62±0.12 , respectively). Although differences were seen in a group analysis, the healthy patient Dice coefficients spanned a wide range, limiting the diagnostic capabilities of this SO 2 SO2 symmetry analysis on an individual basis. Our results suggest that for assessing the SO 2 SO2 contrast of breast lesions, it may be better to select a reference tissue in the ipsilateral rather than the contralateral breast.

Broadband optical mammography: chromophore concentration and hemoglobin saturation contrast in breast cancer.

This study reports the optical characterization and quantitative oximetry of human breast cancer using spectrally-resolved images collected with a broadband, continuous-wave optical mammography instrument. On twenty-six cancer patients, we collected two-dimensional optical mammograms and created maps of the concentrations of hemoglobin, water, and lipids, as well as the oxygen saturation of hemoglobin. For each cancerous breast, we analyzed the difference between the tumor region (as identified by x-ray and optical mammography) and the remainder of breast tissue. With respect to the surrounding tissue, we found that cancer regions have significantly higher concentrations of total hemoglobin (+2.4 ± 0.4 µM) and water (+7 ± 1% v/v), and significantly lower lipid concentration (8 ± 2% v/v) and oxygen saturation of hemoglobin (5 ± 1%). We also found a significant correlation between the tumor optical contrast and the grade of breast cancer as quantified by the Nottingham histologic score; this demonstrates how optical signatures may be representative of metabolic and morphological features, as well as the aggressive potential of the tumor.

Efficacy and safety of continuous low-irradiance photodynamic therapy in the treatment of chest wall progression of breast cancer.

BACKGROUND: Photodynamic therapy (PDT) is a binary therapy using a drug and high-energy light source. PDT is approved for several premalignant and malignant conditions. Recent in-vitro and animal data suggest that enhanced tumor-specific cytotoxicity can be achieved with far less collateral damage to normal surrounding tissues if PDT is administered continuously at a lower dose rate for extended periods of time. Based on these promising preclinical data, we conducted a Phase I clinical trial of continuous low-irradiance photodynamic therapy (CLIPT) using 630 nm laser energy and intravenously administered porforin sodium as the photosensitizer. We determined the maximum tolerated dose (MTD) of CLIPT on skin and tumor response in subjects with cutaneous and subcutaneous metastatic nodules who had failed radiation and surgery. METHODS: Patients with cutaneous and/or subcutaneous metastatic nodules that had failed radiation and surgery were offered enrollment into the trial. The initial study design planned for sequential cohorts of six subjects to be treated at increasing laser intensity, starting at 100 J/cm(2) administered continuously over 24 h (10(-2) dose rate compared with standard PDT). Dose-limiting toxicity was defined as partial or full-thickness necrosis of the surrounding tumor-free, previously irradiated skin. The MTD was defined as the highest laser energy at which ≤33% of subjects experienced the dose-limiting toxicity. Subjects received intravenous porfirmer sodium 0.8 mg/kg 48 h before commencing CLIPT. Response rates and quality of life measures were assessed. RESULTS: Nine subjects were enrolled with chest wall progression of breast cancer following mastectomy. All had failed prior surgery and electron-beam radiation therapy. The initial two subjects were treated at 100 J/cm(2) and developed partial thickness skin necrosis. Dose reduction was therefore instituted, and the next cohort was treated at 50 J/cm(2). None of the subsequent seven subjects suffered partial or full thickness necrosis, thus establishing the MTD at 50 J/cm(2) over 24 h (0.5 mW irradiance). Six of the nine subjects (67%) had either a complete or partial clinical response. Of note, two subjects had significant regression of tumor nodules distant from the treatment field. Of the eight subjects whose terminal deoxynucleotidyl transferase dUTP nick end labeling assay results were available, 8 (100%) demonstrated histologic response to treatment as evidenced by either tumor apoptosis or regression. Quality of life measures were improved following treatment-particularly bleeding and pain from the tumor nodules. CONCLUSIONS: The MTD of CLIPT was established at 50 J/cm(2) administered continuously over 24 h. These preliminary data suggest CLIPT may be an effective, low-morbidity therapeutic modality in the treatment of cutaneous and subcutaneous metastases of breast cancer following mastectomy. Further evaluation in a larger cohort is warranted to better assess efficacy and optimize the intervention.

A modified triple test for palpable breast masses: the value of ultrasound and core needle biopsy.

BACKGROUND: The original triple test score (TTS)--clinical examination, mammogram, and fine-needle aspiration (FNA) biopsy--has long been used to evaluate palpable breast masses. We modified the original TTS to include ultrasound (US) and core biopsy to determine their role in evaluating palpable breast masses. METHODS: A retrospective chart review of 320 female patients was performed. We developed a modified triple test score (mTTS) that included physical examination, mammogram and/or US, and FNA and/or core biopsy. For the examination and imaging score, 1-3 points were given for low, moderate, or high suspicion. Biopsy scores were characterized as benign, atypical, or malignant. Final outcome was determined by open biopsy or follow-up greater than 1 year. RESULTS: Physical examination was 92% accurate (95% confidence interval [CI] 0.89-0.96, p < 0.0001) at predicting whether a mass was benign or malignant. Imaging was 88% accurate (95% CI 0.84-0.92, p < 0.0001) and needle biopsy was 95% accurate (95% CI 0.92-0.98, p < 0.0001). The modified triple test was 99% accurate (95% CI 0.98-1.00, p < 0.0001). Each 1-point increment in the mTTS was associated with an increased risk of cancer, with an odds ratio of 9.73 (CI 5.16-18.4, p < 0.0001). For 150 patients, we compared the original TTS with the mTTS. US and core biopsy changed the scores of 24 patients; only three changed clinical management. CONCLUSIONS: For patients with a palpable breast mass and a mTTS score of 3-4, no further assessment is necessary. Those with a mTTS of 8-9 can proceed to definitive therapy. Patients with a mTTS of 5-7 require further assessment. US and/or core biopsy added little to the accuracy or predictive value of the original TTS.

Non-trocar related major retroperitoneal bleeding during laparoscopic appendectomy.

Most of the reported vascular injuries in laparoscopic appendectomies occur during trocar or Veress needle insertions. As laparoscopy continues to evolve, it is essential that surgeons report unusual complications in an effort to raise awareness and guide management of any iatrogenic injury incurred during minimally-invasive procedures. We report the case of a patient who sustained a major non-trocar related retroperitoneal vascular injury during a routine LA.

Mapping the cellular and molecular heterogeneity of normal and malignant breast tissues and cultured cell lines.

INTRODUCTION: Normal and neoplastic breast tissues are comprised of heterogeneous populations of epithelial cells involving various degrees of maturation and differentiation. While cultured cell lines have been derived from both normal and malignant tissues, it remains unclear whether they retain a similar cellular heterogeneity as to that found within breast tissues. METHODS: We used 12 reduction mammoplasty tissues, 15 primary breast cancer tissues, and 20 human breast epithelial cell lines (16 cancer lines, 4 normal lines) to perform flow cytometry for CD44, CD24, epithelial cell adhesion molecule (EpCAM), and CD49f expression as well as immunohistochemistry, and in vivo tumor xenograft formation studies to extensively analyze the molecular and cellular characteristics of breast epithelial cell lineages. RESULTS: Human breast tissues contain four distinguishable epithelial differentiation states (two luminal phenotypes and two basal phenotypes) that differ on the basis of CD24, EpCAM and CD49f expression. Primary human breast cancer tissues also contain these four cellular states, but in altered proportions compared to normal tissues. In contrast, cultured cancer cell lines are enriched for rare basal and mesenchymal phenotypes, which are normally present in small numbers within human tissues. Similarly, cultured normal human mammary epithelial cell lines were enriched for rare basal and mesenchymal phenotypes that represent a minor fraction of cells within reduction mammoplasty tissues. Although normal human mammary epithelial cell lines exhibited features of bi-potent progenitor cells they were unable to differentiate into mature luminal breast epithelial cells. CONCLUSIONS: As a group breast cancer cell lines represent the heterogeneity of human breast tumors, but individually they exhibit increased lineage-restricted profiles that fall short of truly representing the intratumoral heterogeneity of individual breast tumors. Additionally, normal human mammary epithelial cell lines fail to retain much of the cellular diversity found in human breast tissues and are enriched for differentiation states that are a minority in breast tissues, although they do exhibit features of bi-potent basal progenitor cells. These findings suggest that collections of cell lines representing multiple cell types can be used to model the cellular heterogeneity of tissues.

Tumor-derived Cyr61(CCN1) promotes stromal matrix metalloproteinase-1 production and protease-activated receptor 1-dependent migration of breast cancer cells.

Matrix metalloproteinases (MMPs) play a central role in remodeling the tumor-stromal microenvironment. We recently determined that stromal-derived MMP-1 also acts as a signaling molecule by cleaving protease-activated receptor 1 (PAR1) to cause breast cancer cell migration and invasion. Here, we show that ectopic PAR1 expression induces expression of the angiogenic factor Cyr61(CCN1) in breast cancer cells. The tumor-derived Cyr61 acts as an invasogenic signaling molecule that induces MMP-1 expression in adjacent stromal fibroblasts. Gene silencing of Cyr61 in breast cancer cells suppresses MMP-1 induction in stromal fibroblasts resulting in a major loss in migration of the cancer cells toward the fibroblasts. Cyr61-dependent loss of migration was complemented by exogenous MMP-1 and required the presence of the functional PAR1 receptor on the breast cancer cells. These results suggest that interrupting tumor-stromal cell communication by targeting Cyr61 may provide an alternative therapeutic approach for the treatment of invasive breast cancer.

The pancake phenomenon contributes to the inaccuracy of margin assessment in patients with breast cancer.

BACKGROUND: To determine the effect on margin evaluation for patients with breast cancer, we prospectively quantified the "flattening" of the breast specimen after surgical removal. METHODS: The volume and height of 100 consecutive breast biopsy specimens were recorded independently by the operating surgeon and the pathologist. Five factors were analyzed that were thought to contribute to changes in specimen dimensions: patient age, breast tissue density, mammographic lesion type, specimen size, and the use of compression during specimen radiography. RESULTS: After surgical removal, mean volume and height of the breast specimens decreased from 46 cm(3) to 29 cm(3) (30%) and from 2.6 cm to 1.4 cm (46%), respectively. Flattening of the breast specimens occurred in all subgroups studied. CONCLUSIONS: Breast specimens are flattened after surgical removal, losing almost 50% of their original height. This "pancake" phenomenon has important implications for the accuracy of margin analysis.