An Electronic Health Record-based Intervention to Promote Hepatitis C Virus Testing Among Adults Born Between 1945 and 1965: A Cluster-randomized Trial.

BACKGROUND: The Centers for Disease Control and Prevention (CDC) recommends one-time hepatitis C virus (HCV) antibody testing for "Birth Cohort" adults born during 1945-1965. OBJECTIVE: To examine the impact of an electronic health record (EHR)-embedded best practice alert (BPA) for HCV testing among Birth Cohort adults. DESIGN: Cluster-randomized trial was conducted from April 29, 2013 to March 29, 2014. SUBJECTS AND SETTING: Ten community and hospital-based primary care practices. Participants were attending physicians and medical residents during 25,620 study-eligible visits. INTERVENTION: Physicians in all practices received a brief introduction to the CDC testing recommendations. At visits for eligible patients at intervention sites, physicians received a BPA through the EHR to order HCV testing or medical assistants were prompted to post a testing order for the physician. Physicians in control sites did not receive the BPA. MAIN OUTCOMES: HCV testing; the incidence of HCV antibody positive tests was a secondary outcome. RESULTS: Testing rates were greater among Birth Cohort patients in intervention sites (20.2% vs. 1.8%, P<0.0001) and the odds of testing were greater in intervention sites after controlling for imbalances of patient and visit characteristics between comparison groups [odds ratio (OR), 9.0; 95% confidence interval, 7.6-10.7). The adjusted OR of identifying HCV antibody positive patients was also greater in intervention sites (OR, 2.1; 95% confidence interval, 1.3-11.2). CONCLUSIONS: An EHR-embedded BPA markedly increased HCV testing among Birth Cohort patients, but the majority of eligible patients did not receive testing indicating a need for more effective methods to promote uptake.

TARGIT-R (Retrospective): North American Experience with Intraoperative Radiation Using Low-Kilovoltage X-Rays for Breast Cancer.

BACKGROUND: Single-dose intraoperative radiotherapy (IORT) is an emerging treatment for women with early stage breast cancer. The objective of this study was to define the frequency of IORT use, patient selection, and outcomes of patients treated in North America. METHODS: A multi-institutional retrospective registry was created, and 19 institutions using low-kilovoltage IORT for the treatment of breast cancer entered data on patients treated at their institution before July 31, 2013. Patient selection, IORT treatment details, complications, and recurrences were analyzed. RESULTS: From 2007 to July 31, 2013, a total of 935 women were identified and treated with lumpectomy and IORT. A total of 822 patients had at least 6 months' follow-up documented and were included in the analysis. The number of IORT cases performed increased significantly over time (p < 0.001). The median patient age was 66.8 years. Most patients had disease that was <2 cm in size (90 %) and was estrogen positive (91 %); most patients had invasive ductal cancer (68 %). Of those who had a sentinel lymph node procedure performed, 89 % had negative sentinel lymph nodes. The types of IORT performed were primary IORT in 79 %, secondary IORT in 7 %, or planned boost in 14 %. Complications were low. At a median follow-up of 23.3 months, crude in-breast recurrence was 2.3 % for all patients treated. CONCLUSIONS: IORT use for the treatment of breast cancer is significantly increasing in North America, and physicians are selecting low-risk patients for this treatment option. Low complication and local recurrence rates support IORT as a treatment option for selected women with early stage breast cancer.

A common copy-number breakpoint of ERBB2 amplification in breast cancer colocalizes with a complex block of segmental duplications.

INTRODUCTION: Segmental duplications (low-copy repeats) are the recently duplicated genomic segments in the human genome that display nearly identical (> 90%) sequences and account for about 5% of euchromatic regions. In germline, duplicated segments mediate nonallelic homologous recombination and thus cause both non-disease-causing copy-number variants and genomic disorders. To what extent duplicated segments play a role in somatic DNA rearrangements in cancer remains elusive. Duplicated segments often cluster and form genomic blocks enriched with both direct and inverted repeats (complex genomic regions). Such complex regions could be fragile and play a mechanistic role in the amplification of the ERBB2 gene in breast tumors, because repeated sequences are known to initiate gene amplification in model systems. METHODS: We conducted polymerase chain reaction (PCR)-based assays for primary breast tumors and analyzed publically available array-comparative genomic hybridization data to map a common copy-number breakpoint in ERBB2-amplified primary breast tumors. We further used molecular, bioinformatics, and population-genetics approaches to define duplication contents, structural variants, and haplotypes within the common breakpoint. RESULTS: We found a large (> 300-kb) block of duplicated segments that was colocalized with a common-copy number breakpoint for ERBB2 amplification. The breakpoint that potentially initiated ERBB2 amplification localized in a region 1.5 megabases (Mb) on the telomeric side of ERBB2. The region is very complex, with extensive duplications of KRTAP genes, structural variants, and, as a result, a paucity of single-nucleotide polymorphism (SNP) markers. Duplicated segments are varied in size and degree of sequence homology, indicating that duplications have occurred recurrently during genome evolution. CONCLUSIONS: Amplification of the ERBB2 gene in breast tumors is potentially initiated by a complex region that has unusual genomic features and thus requires rigorous, labor-intensive investigation. The haplotypes we provide could be useful to identify the potential association between the complex region and ERBB2 amplification.

Risk factors for complications of radiation therapy on tissue expander breast reconstructions.

Radiation therapy has been shown to increase complication rates of tissue expander/implant breast reconstructions. The purpose of this study was to evaluate patient characteristics to assess their impact on complications. A retrospective review of patients who underwent mastectomy plus tissue expander/implant reconstruction from January 2000 to December 2006 was performed. The main outcome of interest was the development of postoperative complications. Analyses were performed to detect risk factors for complications. A total of 560 patients were included in the study. A total of 385 patients underwent unilateral and 174 underwent bilateral tissue expander/implant reconstructions, for a total of 733 reconstructions. A total complication rate of 31.8% and a major complication rate of 24.4% were calculated. The risk factors associated with a significantly increased incidence of complications were age greater than 50 years, body mass index (BMI) greater than 30, and radiation. Women younger than 50 years had a complication rate of 28.4%, whereas women older than 50 years had a complication rate of 37.0%. Women with a BMI less than 30 had a complication rate of 27.5%, whereas women with a BMI greater than 30 had a complication rate of 49%. The major complication rate in nonradiated and radiated patients was 21.2% and 45.4%, respectively. Despite higher complication rates, tissue expander/implant reconstructions were successful in 70.1% of radiated patients. Based on this study, the ideal radiated patient would have a BMI less than 30 and be younger than 50 years of age to maximize the likelihood of a successful tissue expander/implant reconstruction.

Complication rates of radiation on tissue expander and autologous tissue breast reconstruction.

BACKGROUND: To evaluate risk factors for complications of tissue expander/implant and autologous tissue breast reconstructions and determine if radiation increases complication rates. MATERIALS AND METHODS: We performed a retrospective review of patients who underwent mastectomy plus autologous tissue or expander/implant reconstruction at the Cleveland Clinic. Univariate and multivariate analysis were performed in each group to evaluate for risk factors for complications. A complication was considered major if it required reoperation. A predictive model was used to compare the 2 groups to one another. RESULTS: A total of 1037 patients were included in the study. In the tissue expander/implant population, there was a total complication rate of 31.8% and overall major complication rate of 24.4%. Radiation increased the major complication rate from 21.2 to 45.4%. However, 70.1% of the radiated patients ultimately had a successful implant-based reconstruction while an additional 10.3% went on to have autologous reconstruction. Age and body mass index (BMI) > 30 also led to higher major complication rates in tissue expander/implant reconstruction while smoking, hypertension, and chemotherapy had no impact. In the autologous reconstruction group, there was a total complication rate of 31.5% and a major complication rate of 19.7%. There was no statistically significant difference between the radiated and nonradiated autologous tissue reconstructions with major complication rates of 17.9 and 20.5%, respectively. BMI > 30 was the only significant factor leading to higher major complications in the autologous reconstructions. CONCLUSION: Total complication rates were similar between tissue expander and autologous reconstructions. Increased major complication rates in patients with tissue expander reconstructions occurred in those with radiation, but was still successful in the majority of patients. Radiation had no influence on autologous tissue reconstruction major complication rates.

The 76-gene signature defines high-risk patients that benefit from adjuvant tamoxifen therapy.

PURPOSE: To assess the benefit from adjuvant systemic tamoxifen therapy in breast cancer risk groups identified by the previously established prognostic 76-gene signature. METHODS: In 300 lymph node-negative (LNN), estrogen receptor-positive (ER+) breast cancer patients (136 treated with adjuvant tamoxifen, 164 having received no systemic adjuvant therapy), distant metastasis-free survival (DMFS) as a function of the 76-gene signature was determined in a multicenter fashion. RESULTS: In 136 tamoxifen-treated patients, the 76-gene signature identified a group of patients with a poor prognosis [hazard ratio (HR), 4.62; P = 0.0248]. These patients showed a 12.3% absolute benefit of tamoxifen in 10-year DMFS (HR, 0.52; P = 0.0318) compared with untreated high-risk patients. This represented a 71% increase in relative benefit compared with the 7.2% absolute benefit observed for all 300 patients without using the gene signature. In the low-risk group there was no significant 10-year DMFS benefit of tamoxifen. CONCLUSIONS: The 76-gene signature defines high-risk patients who benefit from adjuvant tamoxifen therapy. Although we did not study the value of chemotherapy in this study, low-risk patients identified by the 76-gene signature have a prognosis good enough that chemotherapy would be difficult to justify. The prognosis of these patients is sufficiently good, in fact, that a disease-free benefit for tamoxifen therapy is difficult to prove, though benefits in terms of loco-regional relapse and a reduction in risk for contralateral breast cancer might justify hormonal therapy in these patients.

In vivo margin assessment during partial mastectomy breast surgery using raman spectroscopy.

We present the first demonstration of in vivo collection of Raman spectra of breast tissue. Raman spectroscopy, which analyzes molecular vibrations, is a promising new technique for the diagnosis of breast cancer. We have collected 31 Raman spectra from nine patients undergoing partial mastectomy procedures to show the feasibility of in vivo Raman spectroscopy for intraoperative margin assessment. The data was fit with an established model, resulting in spectral-based tissue characterization in only 1 second. Application of our previously developed diagnostic algorithm resulted in perfect sensitivity and specificity for distinguishing cancerous from normal and benign tissues in our small data set. Significantly, we have detected a grossly invisible cancer that, upon pathologic review, required the patient to undergo a second surgical procedure. Had Raman spectroscopy been used in a real-time fashion to guide tissue excision during the procedure, the additional reexcision surgery might have been avoided. These preliminary findings suggest that Raman spectroscopy has the potential to lessen the need for reexcision surgeries resulting from positive margins and thereby reduce the recurrence rate of breast cancer following partial mastectomy surgeries.

Time-Related Changes in Yield and Harms of Screening Breast Magnetic Resonance Imaging.

PURPOSE: Breast magnetic resonance imaging (MRI) is accepted as a useful adjunct to screening mammography for women at high risk for breast cancer. Nevertheless, concerns about false-positive findings remain, and data about MRI harms and yields are limited. The aim of this study was to quantify harms and yields of breast MRI over time in a large series of patients. METHODS: A retrospective review was performed of patients at increased risk for breast cancer who underwent annual screening digital mammography and MRI from 2007 to 2013. Harms were defined as events not producing a breast cancer diagnosis (ultrasonography [US], imaging-guided core or surgical biopsy procedure, recommendation for short-term follow-up, or a combination). RESULTS: Of 350 high-risk patients offered MRI screening, 320 underwent 757 screening MRI procedures over time. The median age at the first MRI was 48 years. All patients met American Cancer Society criteria for annual screening breast MRI. Total harms were highest with the first MRI procedure and decreased with subsequent MRI screening. Of 75 biopsy procedures performed, including 58 US- or MRI-guided core biopsy procedures and 17 surgical biopsy procedures, 6 specimens were found to be malignant, including 2 resulting from biopsy procedures performed based on findings from the first MRI scan, 0 from the second MRI scan, 3 from the third MRI scan, and 1 from the fourth MRI scan. CONCLUSION: Among women followed with screening MRI, the number of harms was shown to decrease over time. Breast cancer continued to be detected in MRI studies performed over time. This study demonstrates the utility of MRI screening performed over time in high-risk women.

Conservative axillary surgery in breast cancer patients undergoing mastectomy: long-term results.

BACKGROUND: Recently, the American College of Surgeons Oncology Group Z0011 trial demonstrated that axillary lymph node dissection (ALND) could be safely avoided in selected breast cancer patients with limited nodal disease and having breast conservation therapy. However, for node positive (N+) mastectomy patients, full ALND remains the standard of care. Hypothesizing that omission of complete ALND is safe in many N+ breast cancer patients, a hybrid procedure called conservative axillary regional excision (CARE) was developed, consisting of removal of sentinel nodes and other palpable nodes (without intraoperative frozen section or reoperation for N+). STUDY DESIGN: A retrospective review of patients undergoing mastectomy with CARE between 2002 and 2010 was performed. Data collected included demographics; staging; number of lymph nodes removed; adjuvant, antihormonal, and radiation therapies; recurrence; lymphedema; and survival data. Recurrence-free survival was estimated using the Kaplan-Meier method and compared using Cox proportional hazards. RESULTS: Five hundred and eighty-seven patients underwent mastectomy with CARE. Mean follow-up was 5.1 years. A median of 8 nodes were removed. There were 7 patients with local recurrence, of which 3 were axillary recurrences. Lymphedema developed in 20 (3.4%) patients, 75% of which had neoadjuvant chemotherapy. Lymphedema development was associated with the number of lymph nodes removed (p = 0.05) and radiation therapy (p = 0.004). CONCLUSIONS: Conservative axillary regional excision is an excellent model for understanding the role of limited axillary surgery in mastectomy patients. The locoregional recurrence rate among N1 patients having CARE is low (3.4%). Conservative axillary regional excision is also associated with low rates of lymphedema. These data support the use of limited ALND in selected N+ mastectomy patients.