The Aplastic Crisis in HbSS: Observations from the Jamaican Birth Cohort.

In order to document the prevalence, clinical features, hematology and outcome of the aplastic crisis in homozygous sickle cell disease (HbSS), a cohort study has been conducted from birth. Newborn screening of 100 000 deliveries at the main government maternity hospital, Kingston, Jamaica between 1973 and 1981 detected 311 cases of HbSS who have been followed at the Medical Research Council Laboratories at the University of the West Indies, Kingston, Jamaica. Clinically defined aplastic crises occurred in 118 (38%) patients at a median age of 7.5 years (range 0.5-23.0 years). All but one event seroconverted to parvovirus B19, the exception being a 9.3 year male with classic aplasia but subsequent IgG did not exceed 3 IU. Defined by zero reticulocyte counts, 94 patients presented with a median hemoglobin of 3.7 g/dL (range 18-87 g/L) representing a median fall from steady state levels of 3.8 g/dL. Clear epidemic peaks occurred at 1979-1980, 1984-1986, and 1990-1993 and the admission rate and use of blood cultures fell with each epidemic, reflecting increased familiarity with the complication. Symptoms were usually nonspecific and all but 7 were transfused. No patient had a recurrence and two died from aplasia (one with remote rural residence and the other following an incorrect diagnosis). Of those seroconverting to parvovirus B19, 68% manifested aplasia and 24% had no hematologic change. Correctly diagnosed and managed, the aplastic crisis is essentially benign. (230 words).

Cost-Effectiveness Analysis: Lymph Node Transfer vs Lymphovenous Bypass for Breast Cancer-Related Lymphedema.

BACKGROUND: Lymph node transfer (LNT) and lymphovenous bypass (LVB) have been described as 2 major surgical options for patients with breast cancer-related lymphedema (BCRL) who have failed conservative therapy. The objective of our study was to perform a cost-effectiveness analysis comparing LNT and LVB for the treatment of BCRL. STUDY DESIGN: Rates of infection, lymph leak, and failure of LNT and LVB were obtained from a previously published meta-analysis. Failure of surgery was defined as the inability to cease compression therapy postoperatively. Procedural costs were calculated from Medicare reimbursement rates. Cost of conservative management of postoperative surgical site infection, lymph leak, and continued decongestive physiotherapy after failed surgery were obtained from literature review. Average utility scores for each health state were calculated using a visual analog scale survey, then converted to quality-adjusted life years (QALYs). A decision tree was constructed, and incremental cost-effectiveness ratio was assessed at $50,000/QALY. Deterministic and probabilistic sensitivity analyses were performed to evaluate the robustness of our findings. RESULTS: LNT was less costly ($22,492 vs $31,927) and more effective (31.82 QALY vs 29.24 QALY) than LVB. One-way (deterministic) sensitivity analysis demonstrated that LNT became cost-ineffective when its failure rate was more than 43.8%. LVB became more cost-effective than LNT when its failure rate was less than 21.4%. Probabilistic sensitivity analysis using Monte-Carlo simulation indicated that even with uncertainty present in the variables analyzed, the majority of simulations (97%) favored LNT as the more cost-effective strategy. CONCLUSIONS: LNT is a dominant, cost-effective strategy compared to LVB for the treatment of BCRL.

Modelling early events in Mycobacterium bovis infection using a co-culture model of the bovine alveolus.

Bovine tuberculosis (bTB), a zoonosis mainly caused by Mycobacterium bovis has severe socio-economic consequences and impact on animal health. Host-pathogen interactions during M. bovis infection are poorly understood, especially early events which are difficult to follow in vivo. This study describes the utilisation of an in vitro co-culture model, comprising immortalised bovine alveolar type II (BATII) epithelial cells and bovine pulmonary arterial endothelial cells (BPAECs). When cultured at air-liquid interface, it was possible to follow the migration of live M. bovis Bacille Calmette-Guérin (BCG) and to observe interactions with each cell type, alongside cytokine release. Infection with BCG was shown to exert a detrimental effect primarily upon epithelial cells, with corresponding increases in IL8, TNFα, IL22 and IL17a cytokine release, quantified by ELISA. BCG infection increased expression of CD54, MHC Class I and II molecules in endothelial but not epithelial cells, which exhibited constitutive expression. The effect of peripheral blood mononuclear cell conditioned medium from vaccinated cattle upon apical-basolateral migration of BCG was examined by quantifying recovered BCG from the apical, membrane and basolateral fractions over time. The numbers of recovered BCG in each fraction were unaffected by the presence of PBMC conditioned medium, with no observable differences between vaccinated and naïve animals.

Homozygous sickle cell disease in Central India & Jamaica: A comparison of newborn cohorts.

Background & objectives: Homozygous sickle cell (SS) disease in Central India runs a more severe clinical course than reports from other areas of India. The current study was undertaken to compare the disease in Central India (Nagpur) with that in Jamaica, both populations defined by newborn screening. Methods: The Nagpur cohort included infants born to sickling-positive mothers from May 2008 to 2012, examined by high-pressure liquid chromatography and DNA analysis. The Jamaican cohort screened 100,000 consecutive non-operative deliveries between June 1973 and December 1981, analyzed by haemoglobin (Hb) electrophoresis and confirmed by family studies and compatible HbA2levels. Results: In Nagpur, 103 SS patients were detected, but only 78 (76%) were followed up. In Jamaica, 311 cases were followed from birth and compliance with follow up remained 100 per cent up to 45 years. In the Nagpur cohort all had the Asian haplotype, and 82 per cent of Jamaicans had at least one Benin chromosome; none had the Asian haplotype. Compared to Jamaica, Nagpur patients had higher foetal Hb, less alpha-thalassaemia, later development of splenomegaly and less dactylitis. There were also high admission rates for febrile illness and marked anaemia. Invasive pneumococcal disease occurred in 10 per cent of Jamaicans but was not seen in Nagpur. Interpretation & conclusions: There were many differences between the disease in Nagpur, Central India and the African form observed in Jamaica. The causes of severe anaemia in Nagpur require further study, and reticulocyte counts may be recommended as a routine parameter in the management of SS disease. The role of pneumococcal prophylaxis needs to be determined in Nagpur patients. Future studies in India must avoid high default rates.

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.

Trending Towards Safer Breast Cancer Surgeries? Examining Acute Complication Rates from A 13-Year NSQIP Analysis.

As breast cancer surgery continues to evolve, this study highlights the acute complication rates and predisposing risks following partial mastectomy (PM), mastectomy(M), mastectomy with muscular flap reconstruction (M + MF), mastectomy with implant reconstruction (M + I), and oncoplastic surgery (OPS). Data was collected from the American College of Surgeons NSQIP database (2005⁻2017). Complication rate and trend analyses were performed along with an assessment of odds ratios for predisposing risk factors using adjusted linear regression. 226,899 patients met the inclusion criteria. Complication rates have steadily increased in all mastectomy groups (p < 0.05). Cumulative complication rates between surgical categories were significantly different in each complication cluster (all p < 0.0001). Overall complication rates were: PM: 2.25%, OPS: 3.2%, M: 6.56%, M + MF: 13.04% and M + I: 5.68%. The most common predictive risk factors were mastectomy, increasing operative time, ASA class, BMI, smoking, recent weight loss, history of CHF, COPD and bleeding disorders (all p < 0.001). Patients who were non-diabetic, younger (age < 60) and treated as an outpatient all had protective OR for an acute complication (p < 0.0001). This study provides data comparing nationwide acute complication rates following different breast cancer surgeries. These can be used to inform patients during surgical decision making.

Surgical trends in breast cancer: a rise in novel operative treatment options over a 12 year analysis.

PURPOSE: Breast cancer surgical techniques are evolving. Few studies have analyzed national trends for the multitude of surgical options that include partial mastectomy (PM), mastectomy without reconstruction (M), mastectomy with reconstruction (M+R), and PM with oncoplastic reconstruction (OS). We hypothesize that the use of M is declining and likely correlates with the rise of surgery with reconstructive options (M+R, OS). METHODS: A retrospective cohort analysis was conducted using the ACS-NSQIP database from 2005 to 2016 and ICD codes for IBC and DCIS. Patients were then grouped together based on current procedural terminology (CPT) codes for PM, M, M+R, and OS. In each group, categories were sorted again based on additional reconstructive procedures. Data analysis was conducted via Pearson's chi-squared test for demographics, linear regression, and a non-parametric Mann- Kendall test to assess a temporal trend. RESULTS: The patient cohort consisted of 256,398 patients from the NSQIP data base; 197,387 meet inclusion criteria diagnosed with IBC or DCIS. Annual breast surgery trends changed as follows: PM 46.3-46.1% (p = 0.21), M 35.8-26.4% (p = 0.001), M+R 15.9-23.0% (p = 0.03), and OS 1.8-4.42% (p = 0.001). Analyzing the patient cohort who underwent breast conservation, categorical analysis showed a decreased use of PM alone (96-91%) with an increased use of OS (4-9%). For the patient cohort undergoing mastectomy, M alone decreased (69-53%); M+R with muscular flap decreased (9-2%); and M+R with implant placement increased (20-40%)-all three trends p < 0.0001. CONCLUSION: The modern era of breast surgery is identified by the increasing use of reconstruction for patients undergoing breast conservation (in the form of OS) and mastectomy (in the form of M+R). Our study provides data showing significant trends that will impact the future of both breast cancer surgery and breast training programs.

The underreporting of cost perspective in cost-analysis research: A systematic review of the plastic surgery literature.

BACKGROUND: Cost-analysis research can influence healthcare policies and practices. There is inherent bias depending on the chosen cost perspective (hospital, third-party payer, societal), and conclusions can change based on the perspective used. These perspectives may or may not be well declared or justified when performing cost-analysis research. The goal of this study was to perform a literature review of cost-analysis research in the Plastic Surgery literature to determine the prevalence of studies declaring and justifying their perspective, and to inform the reader on why such declarations are important in understanding potential bias. METHODS: A systematic review was completed to retrieve cost-utility and cost-effectiveness research within the scope of Plastic Surgery. The search was limited to English-language studies in North America and Europe published between 2006 and 2016. Articles were selected using predefined data fields and specific inclusion criteria. RESULTS: A total of 2304 abstracts were identified, of which 47 met inclusion criteria. Seventy-two percent of studies (n = 34) declared a cost perspective. Of the studies that identified a cost perspective, 32% incorrectly identified the cost perspective. Only 49% of all studies (n = 23) both accurately declared and justified their chosen perspective. CONCLUSIONS: Only half of studies correctly declare their cost perspective and justify why the perspective was chosen. Not doing so potentially hides bias from the reader. Future efforts when performing cost-analysis studies should require a clear declaration and justification of the cost perspective taken. A table of our recommendations for reporting cost perspective is provided.

Resident and fellow participation in Thyroid and Parathyroid surgery: an ACS-NSQIP clinical outcomes analysis.

BACKGROUND: The effect of decreased overall hours of training in surgical specialties is still being examined. Of particular interest is the safety of patients undergoing surgeries with trainee surgeons. The aim of this study was to identify if there were significant differences in outcomes of patients undergoing commonly performed thyroid and parathyroid surgeries when trainees were involved. MATERIALS AND METHODS: Postoperative complication rates, length of stay (LOS), and total operation time (OT) data were gathered from the American College of Surgeons National Surgical Quality Improvement Project database. The cases were identified by CPT code and were divided based on the training level of the participating resident surgeon: Junior (postgraduate year [PGY] 1-2), senior (PGY 3-5), fellow (PGY >5), as well as an attending-only group where no resident was present. We compared the clinical outcomes, LOS, and OT in each trainee group to the attending-only group as the reference. RESULTS: A total of 84,711 cases were identified of which 45.33% involved trainee participation. Odds ratios (ORs) and 95% confidence interval for overall, neurologic, and bleeding complications were calculated. No difference in the odds of overall patient complications or neurologic complications was observed. A decrease in the odds of bleedings complications when a junior or senior trainee was present was observed. Overall complications in operations including a junior trainee (PGY 1-2) had an OR of 1.04 (0.85, 1.29), a senior trainee (PGY 3-5) had an OR of 1.00 (0.89, 1.13), and a fellow had an OR of 0.98 (0.74, 1.31). Mean OT was found to be significantly different between attending only and junior and senior trainees. There was no significant difference in OT between fellows and attending only. LOS did not meaningfully differ across groups. CONCLUSIONS: In three commonly performed thyroid and parathyroid operations, there is not an increased overall or neurologic complication odds when a surgical trainee is involved; there are decreased odds of a bleeding complication.

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.

Intralesional bleomycin for the treatment of hemangiomas.

BACKGROUND: Hemangiomas, although often small at birth, enter a proliferative phase in which growth may be rapid and unpredictable. Furthermore, involution often takes many years, with attendant psychological sequelae to the child. This is aggravated by the fact that most hemangiomas affect the head and neck and are visible and difficult to conceal. METHODS: Thirty children (five boys and 25 girls) were treated at a pediatric teaching hospital during an 18-month period with a protocol of intralesional bleomycin, 0.3 to 0.6 mg/kg (per dose), administered under general anesthesia. The lesions were measured and photographed serially. Complications were also recorded. RESULTS: The mean age of the children was 20 months (range, 3 months to 8 years) and the mean number of injections given was five (range, three to eight). The mean total dose administered was 13.6 mg (range, 1.4 to 25 mg). Outcome was assessed by a panel of five plastic surgeons. Twenty-two children were assessed as achieving a response of greater than 75 percent reduction in the size of the hemangioma (of which 10 children were assessed as having total involution >90 percent response). In seven children, there was a 50 to 75 percent reduction in size of the hemangiomas, and one child was judged to have a 25 to 50 percent reduction in size of the hemangioma. Hyperpigmentation was the most common complication, and occurred in 13 children. The mean follow-up period was 14 months (range, 3 to 35 months). CONCLUSIONS: Intralesional bleomycin is another method with which to treat hemangiomas in children and may be particularly helpful for large hemangiomas of the head and neck. Repeated general anesthetics are required, and scarring with hyperpigmentation may occur.