Luminal breast epithelial cells from wildtype and BRCA mutation carriers harbor copy number alterations commonly associated with breast cancer.

Cancer-associated mutations have been documented in normal tissues, but the prevalence and nature of somatic copy number alterations and their role in tumor initiation and evolution is not well understood. Here, using single cell DNA sequencing, we describe the landscape of CNAs in >42,000 breast epithelial cells from women with normal or high risk of developing breast cancer. Accumulation of individual cells with one or two of a specific subset of CNAs (e.g. 1q gain and 16q, 22q, 7q, and 10q loss) is detectable in almost all breast tissues and, in those from BRCA1 or BRCA2 mutations carriers, occurs prior to loss of heterozygosity (LOH) of the wildtype alleles. These CNAs, which are among the most common associated with ductal carcinoma in situ (DCIS) and malignant breast tumors, are enriched almost exclusively in luminal cells not basal myoepithelial cells. Allele-specific analysis of the enriched CNAs reveals that each allele was independently altered, demonstrating convergent evolution of these CNAs in an individual breast. Tissues from BRCA1 or BRCA2 mutation carriers contain a small percentage of cells with extreme aneuploidy, featuring loss of TP53 , LOH of BRCA1 or BRCA2 , and multiple breast cancer-associated CNAs in addition to one or more of the common CNAs in 1q, 10q or 16q. Notably, cells with intermediate levels of CNAs are not detected, arguing against a stepwise gradual accumulation of CNAs. Overall, our findings demonstrate that chromosomal alterations in normal breast epithelium partially mirror those of established cancer genomes and are chromosome- and cell lineage-specific.

Single-cell genomic variation induced by mutational processes in cancer.

How cell-to-cell copy number alterations that underpin genomic instability1 in human cancers drive genomic and phenotypic variation, and consequently the evolution of cancer2, remains understudied. Here, by applying scaled single-cell whole-genome sequencing3 to wild-type, TP53-deficient and TP53-deficient;BRCA1-deficient or TP53-deficient;BRCA2-deficient mammary epithelial cells (13,818 genomes), and to primary triple-negative breast cancer (TNBC) and high-grade serous ovarian cancer (HGSC) cells (22,057 genomes), we identify three distinct 'foreground' mutational patterns that are defined by cell-to-cell structural variation. Cell- and clone-specific high-level amplifications, parallel haplotype-specific copy number alterations and copy number segment length variation (serrate structural variations) had measurable phenotypic and evolutionary consequences. In TNBC and HGSC, clone-specific high-level amplifications in known oncogenes were highly prevalent in tumours bearing fold-back inversions, relative to tumours with homologous recombination deficiency, and were associated with increased clone-to-clone phenotypic variation. Parallel haplotype-specific alterations were also commonly observed, leading to phylogenetic evolutionary diversity and clone-specific mono-allelic expression. Serrate variants were increased in tumours with fold-back inversions and were highly correlated with increased genomic diversity of cellular populations. Together, our findings show that cell-to-cell structural variation contributes to the origins of phenotypic and evolutionary diversity in TNBC and HGSC, and provide insight into the genomic and mutational states of individual cancer cells.

Donor-site preferences in women during autologous skin grafting.

BACKGROUND: Autologous split-thickness skin grafting has been proven to provide the best cosmetic and functional outcome after cutaneous burn injuries and thus is the standard of care. Clinical observations have shown that female burn patients frequently have greater difficulty choosing a donor site than do male burn patients. However, there is a lack of data characterizing donor-site preferences among women with burns. METHODS: The purpose of this study was to examine donor-site preferences among women using an online survey that included 356 responders between January 4, 2012, and April 4, 2012. RESULTS: This study found that there was a preference for posterior donor sites, with lower back, left buttock, and left posterior thigh being the most preferred sites. The least preferred locations were the right anterior upper arm, any aspect of the forearms, and the chest. Those surveyed and reporting a higher education level or concerns with scarring were least likely to choose anterior locations. Age, concern for color changes, and prior surgery or grafting had no statistically significant effect on donor-site preference. CONCLUSION: Given these strong preferences among female patients, posterior donor sites should be considered and discussed as compared with the current standard of using lateral or anterior thigh donor sites.

Cost-effectiveness comparison between topical silver sulfadiazine and enclosed silver dressing for partial-thickness burn treatment.

The standard treatment of partial-thickness burns includes topical silver products such as silver sulfadiazine (SSD) cream and enclosed dressings including silver-impregnated foam (Mepilex Ag; Molnlycke Health Care, Gothenburg, Sweden) and silver-laden sheets (Aquacel Ag; ConvaTec, Skillman, NJ). The current state of health care is limited by resources, with an emphasis on evidence-based outcomes and cost-effective treatments. This study includes a decision analysis with an incremental cost-utility ratio comparing enclosed silver dressings with SSD in partial-thickness burn patients with TBSA less than 20%. A comprehensive literature review was conducted to identify clinically relevant health states in partial-thickness burn patients. These health states include successful healing, infection, and noninfected delayed healing requiring either surgery or conservative management. The probabilities of these health states were combined with Medicare CPT reimbursement codes (cost) and patient-derived utilities to fit into the decision model. Utilities were obtained using a visual analog scale during patient interviews. Expected cost and quality-adjusted life years (QALYs) were calculated using the roll-back method. The incremental cost-utility ratio for enclosed silver dressing relative to SSD was $40,167.99/QALY. One-way sensitivity analysis of complication rates confirmed robustness of the model. Assuming a maximum willingness to pay $50,000/QALY, the complication rate for SSD must be 22% or higher for enclosed silver dressing to be cost effective. By varying complication rates for SSD and enclosed silver dressings, the two-way sensitivity analysis demonstrated the cost effectiveness of using enclosed silver dressing at the majority of complication rates for both treatment modalities. Enclosed silver dressings are a cost-effective means of treating partial thickness burns.

Comparing five alternative methods of breast reconstruction surgery: a cost-effectiveness analysis.

BACKGROUND: The purpose of this study was to assess the cost-effectiveness of five standardized procedures for breast reconstruction to delineate the best reconstructive approach in postmastectomy patients in the settings of nonirradiated and irradiated chest walls. METHODS: A decision tree was used to model five breast reconstruction procedures from the provider perspective to evaluate cost-effectiveness. Procedures included autologous flaps with pedicled tissue, autologous flaps with free tissue, latissimus dorsi flaps with breast implants, expanders with implant exchange, and immediate implant placement. All methods were compared with a "do-nothing" alternative. Data for model parameters were collected through a systematic review, and patient health utilities were calculated from an ad hoc survey of reconstructive surgeons. Results were measured in cost (2011 U.S. dollars) per quality-adjusted life-year. Univariate sensitivity analyses and Bayesian multivariate probabilistic sensitivity analysis were conducted. RESULTS: Pedicled autologous tissue and free autologous tissue reconstruction were cost-effective compared with the do-nothing alternative. Pedicled autologous tissue was the slightly more cost-effective of the two. The other procedures were not found to be cost-effective. The results were robust to a number of sensitivity analyses, although the margin between pedicled and free autologous tissue reconstruction is small and affected by some parameter values. CONCLUSIONS: Autologous pedicled tissue was slightly more cost-effective than free tissue reconstruction in irradiated and nonirradiated patients. Implant-based techniques were not cost-effective. This is in agreement with the growing trend at academic institutions to encourage autologous tissue reconstruction because of its natural recreation of the breast contour, suppleness, and resiliency in the setting of irradiated recipient beds.

A comparison of acellular dermal matrix to autologous dermal flaps in single-stage, implant-based immediate breast reconstruction: a cost-effectiveness analysis.

BACKGROUND: The use of acellular dermal matrix has allowed for single-stage immediate breast reconstruction after mastectomy at a significantly decreased cost compared with two-stage expander/implant reconstruction. The use of a pedicled autologous dermal flap in the same fashion as acellular dermal matrix in women with larger, ptotic breasts has also allowed for single-stage immediate breast reconstruction with similarly low complication rates and without the added procedural cost of using acellular dermal matrix. There have been no prior studies evaluating whether the added procedural cost for acellular dermal matrix is cost-effective relative to using an autologous dermal flap in single-stage immediate breast reconstruction following mastectomy. METHODS: A comprehensive literature review was conducted to identify published complication rates for single-stage, implant-based immediate breast reconstruction using either acellular dermal matrix or an autologous dermal flap. The probabilities of the most common complications were combined with Medicare Current Procedural Terminology reimbursement codes and expert utility estimates to fit into a decision model to evaluate the cost-effectiveness of acellular dermal matrix. RESULTS: : The decision model revealed a baseline cost difference of $261.72 and a 0.001 increase in the quality-adjusted life years when using acellular dermal matrix, yielding an incremental cost-utility ratio of $261,720 per quality-adjusted life year. Sensitivity analysis showed that acellular dermal matrix was not cost-effective when the complication rate for autologous dermal flaps was below 20 percent. CONCLUSIONS: The authors' study demonstrates that acellular dermal matrix is not a cost-effective technology in patients who can have an autologous dermal flap in single-stage immediate breast reconstruction.

A comparison of free autologous breast reconstruction with and without the use of laser-assisted indocyanine green angiography: a cost-effectiveness analysis.

BACKGROUND: Laser-assisted indocyanine green angiography is a U.S. Food and Drug Administration-approved technology used to assess tissue viability and perfusion. Its use in plastic and reconstructive surgery to assess flap perfusion in autologous breast reconstruction is relatively new. There have been no previous studies evaluating the cost-effectiveness of this new technology compared with the current practice of clinical judgment in evaluating tissue perfusion and viability in free autologous breast reconstruction in patients who have undergone mastectomy. METHODS: A comprehensive literature review was performed to identify the complication rate of the most common complications with and without laser-assisted indocyanine green angiography in free autologous breast reconstruction after mastectomy. These probabilities were combined with Medicare Current Procedural Terminology provider reimbursement codes (cost) and utility estimates for common complications from a survey of 10 plastic surgeons to fit into a decision model to evaluate the cost-effectiveness of laser-assisted indocyanine green angiography. RESULTS: The decision model revealed a baseline cost difference of $773.66 and a 0.22 difference in the quality-adjusted life-years, yielding an incremental cost-utility ratio of $3516.64 per quality-adjusted life year favoring laser-assisted indocyanine green angiography. Sensitivity analysis showed that using laser-assisted indocyanine green angiography was more cost-effective when the complication rate without using laser-assisted indocyanine green angiography (clinical judgment alone) was 4 percent or higher. CONCLUSIONS: The authors' study demonstrates that laser-assisted indocyanine green angiography is a cost-effective technology under the most stringent acceptable thresholds when used in immediate free autologous breast reconstruction.

The usefulness of patient-reported measures for clinical practice.

BACKGROUND: The authors assessed the diagnostic potential of commonly used patient-reported measures, namely, the Boston Carpal Tunnel Questionnaire (function and symptom severity), QuickDASH (a shortened version of the Disabilities of the Arm, Shoulder and Hand questionnaire), and the Short Form-8. METHODS: Measure scores were extracted retrospectively from the records of 262 patients (397 hands) and compared using analysis of variance to determine statistical differences among diagnoses assigned by the same surgeon at the time of visit. Patients were grouped into one of two diagnostic groups: those with Dupuytren disease and those with carpal tunnel, osteoarthritis, and tenosynovitis conditions. Logistic regression analysis was performed, and a receiver operating characteristic curve was used in data analysis. RESULTS: Analysis of variance showed statistical differences among the five diagnoses for each patient-reported measure. Results showed that Dupuytren disease was significantly different from the other diagnoses. Carpal tunnel, osteoarthritis, and tenosynovitis conditions were statistically associated with higher Boston Carpal Tunnel Questionnaire function and symptom severity and QuickDASH scores compared with Dupuytren disease. Lower physical and mental summary Short Form-8 scores were associated with the carpal tunnel, osteoarthritis, and tenosynovitis conditions. QuickDASH scores of 25 or higher and Boston Carpal Tunnel Questionnaire symptom severity scores and function scores of 2.5 or higher and of 2 or higher, respectively, are the best patient-reported measure threshold values for distinguishing between the two diagnostic groups. CONCLUSIONS: The QuickDASH and Boston Carpal Tunnel Questionnaire patient-reported measures have diagnostic potential. Establishing threshold values for predicting a diagnostic group may prove to be a useful tool for referring providers. CLINICAL QUESTION/LEVEL OF EVIDENCE: Diagnostic, IV.

A review of lasers and light sources in the treatment of acne vulgaris.

There are various treatment modalities for acne vulgaris including topical and oral therapy as well as microdermabrasion and chemical peels. Recently, there has been an emergence of novel laser and light sources as a means for treating acne vulgaris. This article will review the advances of laser and light sources in the treatment of acne vulgaris.