Evan Matros

BRCA1 promoter methylation in sporadic breast tumors: relationship to gene expression profiles.

BRCA1 is a tumor suppressor gene that functions in DNA repair. Basal-like tumors are a distinctive subtype of breast cancer defined by gene expression profiles. Hereditary BRCA1 breast tumors and basal-like sporadic tumors have a similar phenotype and gene expression signature, suggesting involvement of BRCA1 in the pathogenesis of sporadic basal-like cancer. This study evaluates the role of BRCA1 in sporadic breast tumorigenesis. BRCA1 protein expression and promoter methylation are compared to tumor histopathology and gene expression profiles. We find BRCA1 protein expression correlates with tumor mitotic rate, consistent with normal cell-cycle regulation of the BRCA1 gene. Methylation is found in 21% of tumors and is associated with lower BRCA1 protein, but not with specific pathologic features. Basal-like tumors, defined by hierarchical clustering of gene expression, have infrequent BRCA1 methylation and high levels of BRCA1 protein expression consistent with their high mitotic rate. Tumors with BRCA1 promoter methylation are present in all expression clusters; however, a subgroup of ER-positive high-grade tumors has a significantly greater number of BRCA1 methylated tumors. Absence of BRCA1 promoter methylation and high levels of BRCA1 expression in basal-like sporadic tumors suggest alternate explanations for the phenotypic similarities of these tumors to hereditary BRCA1 tumors.

A paradigm shift in U.S. breast reconstruction: Part 2. The influence of changing mastectomy patterns on reconstructive rate and method.

Background: The aims of the current study were to (1) measure trends in the type of mastectomy performed, (2) evaluate sociodemographic/hospital characteristics of patients undergoing contralateral prophylactic mastectomy versus unilateral mastectomies, and (3) analyze reconstruction rates and method used following different mastectomy types. Methods: Mastectomies from 1998 to 2008 were analyzed using the Nationwide Inpatient Sample database. Mastectomies (n = 178,603) were classified as either unilateral, contralateral prophylactic, or bilateral prophylactic. Reconstructive procedures were categorized into either implant or autologous. Longitudinal trends were analyzed with Poisson regression and sociodemographic/hospital variables were analyzed with logistic regression. Results: Unilateral mastectomies decreased 2 percent per year, whereas contralateral and bilateral prophylactic mastectomies increased significantly by 15 and 12 percent per year, respectively (p < 0.01). Independent predictors for contralateral prophylactic mastectomy (compared with unilateral mastectomy) were patients younger than 39 years, Caucasian and Hispanic race, private insurance carriers, treated in teaching hospitals, and from South and Midwest regions. Contralateral prophylactic mastectomy is the only group with increased reconstruction rates throughout the study period (p < 0.01). Although implant use increased for all mastectomy types, it remains greater in bilateral and contralateral prophylactic mastectomy. Conclusions: There is increasing use of bilateral mastectomies in the United States, particularly in patients with unilateral cancer. Although implant use has increased for all mastectomy types, they are used most commonly following bilateral and contralateral prophylactic mastectomies. Changing mastectomy patterns are one factor underlying the paradigm shift away from autologous tissue to implant-based reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

Systemic siRNA-Mediated Gene Silencing: A New Approach to Targeted Therapy of Cancer

Objective:RNA interference (RNAi), mediated by small interfering RNA (siRNA), silences genes with a high degree of specificity and potentially represents a general approach for molecularly targeted anticancer therapy. The aim of this study was to evaluate the ability of systemically administered siRNA to silence gene expression in vivo and to assess the effect of this approach on tumor growth using a murine pancreatic adenocarcinoma xenograft model. Summary Background Data:Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) is widely overexpressed in human gastrointestinal cancer. Overexpression of CEACAM6 promotes cell survival under anchorage independent conditions, a characteristic associated with tumorigenesis and metastasis. Methods:CEACAM6 expression was quantified by real-time polymerase chain reaction (PCR) and Western blot. Mice (n = 10/group) were subcutaneously xenografted with 2 × 106 BxPC3 cells (which inherently overexpress CEACAM6). Tumor growth, CEACAM6 expression, cellular proliferation (Ki-67 immunohistochemistry), apoptosis, angiogenesis (CD34 immunohistochemistry), and survival were compared for mice administered either systemic CEACAM6-specific or control single-base mismatch siRNA over 6 weeks, following orthotopic tumor implantation. Results:Treatment with CEACAM6-specific siRNA suppressed primary tumor growth by 68% versus control siRNA (P < 0.05) and was associated with a decreased proliferating cell index, impaired angiogenesis and increased apoptosis in the xenografted tumors. CEACAM6-specific siRNA completely inhibited metastasis (0% of mice versus 60%, P < 0.05) and significantly improved survival, without apparent toxicity. Conclusions:Our data demonstrate the efficacy of systemically administered siRNA as a therapeutic modality in experimental pancreatic cancer. This novel therapeutic strategy may be applicable to a broad range of cancers and warrants investigation in patients with refractory disease.

Treatment outcomes associated with surgery for gallbladder cancer: A 20-year experience

The aim of this study was to evaluate contemporary outcomes associated with the management of gallbladder cancer. The medical records of 48 consecutive patients with gallbladder cancer treated at our institution from January 1981 through November 2001 were reviewed. Survival was analyzed using the Kaplan-Meier method (mean follow-up period 24 months) and the log-rank test. Prognostic factors were analyzed using Cox regression. Mean patient age was 68 years. Sixty percent of patients were female. Thirty-nine patients (81%) underwent laparotomy or laparoscopy. Eighteen patients (38%) underwent complete resection (10 simple cholecystectomies and 8 radical cholecystectomies). There were no procedure-related deaths. The overall 5-year survival rate was 13%. Patients who underwent complete resection had a higher 5-year survival rate (31%) than patients who underwent palliative surgery or no surgery (0%; P < 0.05). For patients who underwent radical cholecystectomy, the 5-year survival rate was 60%. For the 18 patients who underwent curative resection, positive lymph node metastasis and patient age over 65 were factors predictive of significantly worse survival. Overall survival rates for patients with gallbladder cancer remain poor. Although radical surgery can be performed safely, it is associated with long-term survival only in a highly select subset of patients with gallbladder cancer.

Vascular considerations in composite midfacial allotransplantation.

Background: Advances in microsurgery and immunosuppression have allowed for facial reconstruction at a qualitatively new level with facial composite tissue allografts. Although donor tissue recovery is unique for each patient, transplantation of the maxilla and overlying soft tissues will be a frequent indication. Vascularity of the maxilla and palate, supplied by facial arteries alone, has been a concern. Based on cadaver dissections and a clinical case, vascular considerations for transplantation of the entire midface are discussed. Methods: To prepare for central facial transplantation in an identified patient, a preclinical dissection was completed on four cadavers. In April of 2009, an extended midfacial allotransplantation was performed. The flap included the entire group of facial mimetic muscles with overlying skin, sensory and motor nerves, nose, upper lip, maxilla, teeth, and hard palate. Results: The preclinical study identified key anatomical structures for inclusion in the composite tissue allograft. Moreover, dissections showed that the facial and angular blood vessels were connected to branches of the maxillary vessels through an anastomotic network organized around the periosteum and bony canals of the midfacial skeleton. Transplantation of a central face allograft including the maxilla and palate was anticipated to be feasible. A technically successful clinical case was completed. Conclusions: Anatomical and clinical observations elucidated several technical points related to composite tissue transplantation of the midface. Careful graft harvest, appropriate selection of donor and recipient vessels, complete allograft revascularization, and restoration of sensory and motor function are critical to making face transplant surgery safe and functional.

The influence of sociodemographic factors and hospital characteristics on the method of breast reconstruction, including microsurgery: a U.S. population-based study.

Background: Microsurgical breast reconstruction has gained popularity because of associations with decreased abdominal morbidity and high satisfaction. Nationwide use of these procedures is unknown. Although many factors can influence the method of breast reconstruction, sociodemographic and hospital characteristics have not been specifically evaluated. The authors studied the importance of microsurgical flaps among the techniques available for breast reconstruction and evaluated the effect of sociodemographic and hospital characteristics on the technique chosen. Methods: A cross-sectional study of breast reconstructions was performed using the Nationwide Inpatient Sample database for 2008. National estimates of breast reconstructive procedures including microsurgery were obtained. Impact of variables on reconstructive method was analyzed using logistic regression. Results: Among women undergoing breast reconstruction in 2008, implants were the most common procedure (60.5 percent), followed by pedicled flaps (34 percent) and microsurgical flaps (5.5 percent). Multivariable analysis showed that women aged 50 to 59 years, treated at teaching hospitals, with private insurance, or undergoing delayed reconstruction were more likely to have autologous than implant reconstruction. Implant use was associated with young patients, Caucasians, Asians, higher income, and all regions except the Northeast. Analysis of autologous reconstructions showed the likelihood for a microsurgical versus a pedicle flap was greater in teaching hospitals, private insurance carriers, and delayed reconstructions. Conclusions: Microsurgical techniques are currently used in only a minority of reconstructions. Sociodemographic variables and teaching hospital status influence the method of breast reconstruction. The presence of disparities in care suggests that current decision making for breast reconstruction is not based solely on patient preference or anatomical features.

What Is the Optimum Timing of Postmastectomy Radiotherapy in Two-Stage Prosthetic Reconstruction: Radiation to the Tissue Expander or Permanent Implant?

Background: Postmastectomy radiotherapy is increasingly common for patients with advanced breast cancer. The optimal timing and sequence of mastectomy, reconstruction, and radiotherapy remains unresolved for patients choosing immediate two-stage prosthetic reconstruction. Methods: Long-term outcomes were compared for all patients with prosthetic-based reconstruction without radiation, radiation to the tissue expander, or to the permanent implant from 2003 to 2012 performed by the senior author (P.G.C.). Surgeon-evaluated outcomes included reconstructive failure, aesthetic results, and capsular contracture. Odds of failure with radiotherapy at different times were evaluated with logistic regression and Kaplan-Meier analysis. Patient-reported outcomes were assessed using the BREAST-Q. Results: A total of 1486 reconstructions without radiation, 94 reconstructions with tissue expander radiation, and 210 reconstructions with permanent implant radiation were included. Six-year predicted failure rates were greater for patients with tissue expander radiation than for patients with permanent implant radiation (32 percent versus 16.4 percent; p < 0.01). Patients undergoing radiation to the tissue expander had a greater proportion of very good to excellent aesthetic results compared to patients with permanent implant radiation (75.0 percent versus 67.6 percent; p < 0.01) and lower rates of grade IV capsular contracture (p < 0.01). BREAST-Q scores were similar for patients with the different radiation timings. Conclusions: Although the risk of reconstructive failure is significantly higher for patients with tissue expander radiation compared to patients with permanent implant radiation, the aesthetic results and capsular contracture rates are slightly better. Patient reported outcomes do not differ between patients with tissue expander or permanent implant radiation. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Reduction in incidence of deep sternal wound infections: Random or real?

OBJECTIVE Comorbidities predisposing cardiac surgical patients toward deep sternal wound infection, such as diabetes and obesity, are rising in the United States. Longitudinal analysis of risk factors, morbidity, and mortality was performed to assessed effects of these health trends on deep sternal wound infection rates. METHODS In this retrospective analysis of all median sternotomies performed at a single institution from 1991 through 2006, demographic and surgical characteristics were identified from a prospective database. The cohort was separated into periods from 1992 through 2001 and 2002 through 2006 to identify longitudinal trends in risk factors for deep sternal wound infection. Univariate and matched multivariable analyses were performed. RESULTS Overall, study population had increased comorbidities associated with deep sternal wound infection such as obesity, diabetes, and advanced age. Deep sternal wound infections were treated in 285 of 21,000 sternotomies performed during study period (1.35%). Deep sternal wound infection rates decreased from 1.57% to 0.88% in last 5 years. Rate of deep sternal wound infection was reduced among patients with diabetes from 3.2% to 1.0%. Multivariable analysis showed diabetes and smoking to be eliminated as risk factors in last 5 years. Prolonged bypass time was the only variable independently associated with deep sternal wound infection for the entire period. Thirty-day and 1-year mortalities for deep sternal wound infection did not change significantly. CONCLUSIONS Analysis of a large series of cardiac surgical patients demonstrates significant reduction in deep sternal wound infection incidence in 15 years. Introduction of perioperative intravenous insulin may explain some observed risk reduction. Efforts should focus on prevention, because mortality remains elevated.

CEACAM6 Is a Novel Biomarker in Pancreatic Adenocarcinoma and PanIN Lesions

Objective:The purpose of this study was to test the hypothesis that CEACAM6 expression is an indicator of adverse pathologic features and clinical outcome in pancreatic adenocarcinoma. Summary Background Data:Previously, we have demonstrated carcinoembryonic antigen–related cell adhesion molecule 6 (CEACAM6) to be an oncoprotein that plays an important role in the biology of pancreatic adenocarcinoma. Suppression of CEACAM6 expression reduces tumorigenesis and metastasis in vivo. Methods:A tissue microarray was constructed using tumor specimens obtained from 89 consecutive patients who had undergone pancreatic resection for pancreatic adenocarcinoma with curative intent. A second microarray containing 54 pancreatic intraepithelial neoplasia (PanIN) lesions was constructed using tissues from a separate cohort of 44 patients. Both arrays were immunostained using a specific anti-CEACAM6 monoclonal antibody. Tumoral CEACAM6 expression was dichotomized into negative and positive immunoreactivity groups. The log-rank test was used to evaluate univariate associations of CEACAM6 expression with prognosis. Survival curves were derived using the Kaplan-Meier method. Results:Tumoral CEACAM6 expression was detected in 82 (92%) pancreatic adenocarcinoma specimens. CEACAM6 expression was more prevalent in high-grade than in low-grade PanIN lesions (P = 0.0002). Negative tumoral CEACAM6 expression was associated with absence of lymph node metastases (P = 0.012), lower disease stage (P = 0.008), and longer postoperative survival (P = 0.047). Conclusions:CEACAM6 is a novel biomarker for pancreatic adenocarcinoma. CEACAM6 warrants further evaluation as both a prognostic factor and a therapeutic target in pancreatic cancer.

Changes in eyebrow position and shape with aging.

Background: Lack of an objective goal for brow-lift surgery may explain why several articles in the plastic surgery literature conclude that brow lifts produce eyebrows with shape and position that are not aesthetically pleasing. By comparing eyebrow shape and position in both young and mature women, this study provides objective data with which to plan forehead rejuvenating procedures. Methods: Two cohorts of women aged 20 to 30 years and 50 to 60 years were photographed to determine eyebrow position. Measurements were made from a horizontal plane between the medial canthi to three points at the upper eyebrow margin. Exclusion criteria included prior surgery, plucked eyebrows, and botulinum toxin. Results: The eyebrow in the 20- to 30-year-old group (n = 36) was 15.7, 19.8, and 21.3 mm above the medial canthus, pupil, and lateral canthus, respectively. Lateral brow position was significantly higher than the mid brow (p < 0.05). In the 50- to 60-year-old group (n = 34), the brow was 19.1, 22.4, and 22.4 mm above the medial canthus, pupil, and lateral canthus, respectively. At all three points, the brow was higher in older compared with younger subjects. This difference was significant at the medial and mid brow (p < 0.05). Conclusions: Unlike other areas of the body where there is descent of soft tissues, there is paradoxical elevation of eyebrows with aging. These findings explain why surgical elevation of the mid and medial brow provides results that are neither youthful nor aesthetically pleasing. Techniques that selectively elevate the lateral brow are more likely to have a rejuvenating effect on the upper third of the female face.