Cost minimization in breast conserving surgery: a comparative study of radiofrequency spectroscopy and full cavity shave margins.

BACKGROUND: In an effort to minimize positive margins and subsequent re-excision after breast conserving surgery (BCS), many providers and facilities have implemented either a Full Cavity Shave (FCS) approach or adding the MarginProbe Radiofrequency Spectroscopy System. OBJECTIVE: We sought to create a functioning Pro-Forma for use by facilities and payers to evaluate and compare the cost savings of implementing FCS or MarginProbe based on personalized variable inputs. METHODS: A decision tree demonstrating three possible surgical pathways, BCS, BCS + FCS, and BCS + MarginProbe was developed with clinical inputs for re-excision rate, mastectomy as 2nd surgery, rate of reconstruction, and rate of 3rd surgery derived by a literature review. A surgical pathway cost formula was created using the decision tree and financial inputs derived by utilizing the nation's largest database of privately billed health insurance claims and Medicare claims data (fairhealth.org). Using the surgical pathway formula and financial inputs, a customizable Pro-Forma was created for immediate cost savings analysis of BCS + FCS and BCS + Marginprobe using variable inputs. Costs are from the perspective of third-party payers. RESULTS: Utilizing MarginProbe to reduce re-excisions for positive margins can be associated with better cost-savings than FCS due to the increased pathology processing costs by using an FCS approach. The reduction in re-excision provided by both FCS and MarginProbe offset their increased expense to various degrees with cost savings of each method improving as baseline re-excisions rates increase, until ultimately each may become cost-neutral or cost-prohibitive when compared to BCS alone. Our data suggest that in the privately insured population, MarginProbe provides a cost-savings over BCS alone when baseline re-excision rates are over 20% and that FCS becomes cost-saving when baseline re-excision rates are over 29%. For Medicare patients, MarginProbe provides a cost-savings when baseline re-excision rates exceed 34%, and FCS becomes cost-saving for re-excision rates over 52%. Our Pro-Forma allows an individual provider or institution to evaluate the cost savings of the FCS approach and/or utilization of the MarginProbe device such that the additional cost or cost-savings of utilizing one or both of these methods can be quickly calculated based on their facility's volume and baseline re-excision rate. CONCLUSIONS: Our data suggest that utilizing either an FCS approach or the MarginProbe radiofrequency spectroscopy system may be a cost-saving solution to reducing the rate of re-excisions depending on a facility or practice's surgical volume and baseline re-excision rate. The degree to which each of these interventions provides an added cost or cost-savings to healthcare payers can be evaluated by utilizing the Pro-Forma outlined herein with customizable variable inputs.

A novel dual-plasmid platform provides scalable transfection yielding improved productivity and packaging across multiple AAV serotypes and genomes.

Transient transfection of mammalian cells using plasmid DNA is a standard method to produce adeno-associated virus (AAV) vectors allowing for flexible and scalable manufacture. Typically, three plasmids are used to encode the necessary components to facilitate vector production; however, a dual-plasmid system, termed pDG, was introduced over 2 decades ago demonstrating two components could be combined resulting in comparable productivity to triple transfection. We have developed a novel dual-plasmid system, pOXB, with an alternative arrangement of sequences that results in significantly increased AAV vector productivity and percentage of full capsids packaged in comparison to the pDG dual design and triple transfection. Here, we demonstrate the reproducibility of these findings across seven recombinant AAV genomes and multiple capsid serotypes as well as the scalability of the pOXB dual-plasmid transfection at 50-L bioreactor scale. Purified drug substance showed a consistent product quality profile in line with triple-transfected vectors, except for a substantial improvement in intact genomes packaged using the pOXB dual- transfection system. Furthermore, pOXB dual- and triple-transfection-based vectors performed consistently in vivo. The pOXB dual plasmid represents an innovation in AAV manufacturing resulting in significant process gains while maintaining the flexibility of a transient transfection platform.

Primary breast diffuse large B cell lymphoma.

Primary breast lymphoma (PBL) is an uncommon type of breast malignancy. Its clinical presentation and radiographic findings are non-specific and overlap with breast carcinoma. The treatment of PBL differs significantly from breast carcinomas. Here we present a middle-aged woman who presented with an enlarging palpable right breast mass. Mammogram showed breast imaging-reporting and data system 4 findings. Breast mass biopsy pathology confirmed diffuse large B cell lymphoma. Although uncommon, clinicians should be cognisant of the possibility of PBL when patients present with a breast mass. Accurate diagnosis is essential to avoid unnecessary mastectomies.

Cryoablation Without Excision for Low-Risk Early-Stage Breast Cancer: 3-Year Interim Analysis of Ipsilateral Breast Tumor Recurrence in the ICE3 Trial.

BACKGROUND: The ICE3 trial is designed to evaluate the safety and efficacy of breast cryoablation, enabling women older than 60 years with low-risk early-stage breast cancers to benefit from a nonsurgical treatment and to avoid the associated surgical risks. METHODS: The ICE3 trial is a prospective, multi-center, single-arm, non-randomized trial including women age 60 years or older with unifocal, ultrasound-visible invasive ductal carcinoma size 1.5 cm or smaller and classified as low to intermediate grade, hormone receptor (HR)-positive, and human epidermal growth factor receptor 2 (HER2)-negative. Ipsilateral breast tumor recurrence (IBTR) at 5 years was the primary outcome. A 3-year interim analysis of IBTR was performed, and the IBTR probability was estimated using the Kaplan-Meier method. RESULTS: Full eligibility for the study was met by 194 patients, who received successful cryoablation per protocol. The mean age was 75 years (range, 55-94 years). The mean tumor length was 8.1 mm (range, 8-14.9 mm), and the mean tumor width was 7.4 mm (range, 2.8-14 mm). During a mean follow-up period of 34.83 months, the IBTR rate was 2.06% (4/194 patients). Device-related adverse events were reported as mild in 18.4% and moderate in 2.4% of the patients. No severe device-related adverse events were reported. More than 95% of the patients and 98% of the physicians reported satisfaction with the cosmetic results at the clinical follow-up evaluation. CONCLUSIONS: Breast cryoablation presents a promising alternative to surgery while offering the benefits of a minimally invasive procedure with minimal risks. Further study within a clinical trial or registry is needed to confirm cryoablation as a viable alternative to surgical excision for appropriately selected low-risk patients.

Underutilization of Needle Biopsy Before Breast Surgery: A Measure of Low-Value Care.

BACKGROUND: Breast core needle biopsy (CNB) can obviate the need for breast surgery in patients with an unknown breast lesion; however, variation in compliance with this guideline may represent a disparity in health care and a surrogate measure of unnecessary surgery. We evaluated variation in breast CNB rates prior to initial breast cancer surgery. METHODS: We performed a retrospective analysis using Medicare claims from 2015 to 2017 to evaluate the proportion of patients who received a CNB within 6 months prior to initial breast cancer surgery. Outlier practice pattern was defined as a preoperative CNB rate ≤ 70%. Logistic regression was used to evaluate surgeon characteristics associated with outlier practice pattern. RESULTS: We identified 108,935 female patients who underwent initial breast cancer surgery performed by 3229 surgeons from July 2015 to June 2017. The mean CNB rate was 86.7%. A total of 7.7% of surgeons had a CNB performed prior to initial breast surgery ≤ 70% of the time, and 2.0% had a CNB performed ≤ 50% of the time. Outlier breast surgeons were associated with practicing in a micropolitan area (odds ratio [OR] 1.88, 95% confidence interval [CI] 1.29-2.73), in the South (OR 1.84, 95% CI 1.20-2.84) or West region (OR 1.78, 95% CI 1.11-2.86), > 20 years in practice (OR 1.52, 95% CI 1.09-2.11), and low breast cancer surgery volume (< 30 cases in the study period; OR 4.03, 95% CI 2.75-5.90). CONCLUSIONS: Marked variation exists in whether a breast core biopsy is performed prior to initial breast surgery, which may represent unnecessary surgery on individual patients. Providing surgeon-specific feedback on guideline compliance may reduce unwarranted variation.

Paget Disease of the Breast in Pregnancy and Lactation.

Paget's disease of the breast (PDB) is a rare breast carcinoma believed to arise from an underlying in situ or invasive ductal cancer that migrates through the epidermis causing characteristic skin changes including scaling, redness, and itching of the nipple, areola, and sometimes the surrounding skin. Although Paget's may mimic benign conditions such as contact or allergic eczema and mastitis, it should remain a strong consideration in the differential diagnosis , especially in peripartum women for whom benign conditions such as bacterial mastitis from breastfeeding are common. The workup of Paget's should focus on both making the diagnosis with nipple/skin scrape cytology or punch biopsy as well as evaluating any underlying mass with mammogram, breast ultrasound , and also a core needle biopsy , if required. Treatment focuses on management of the underlying breast cancer as usual. The purpose of this chapter is to describe the presentation of PDB as well as outline an approach to its diagnosis and management, especially in the setting of pregnancy and lactation.

Analysis of Breast Cancer Patients with T1-2 Tumors and 1-3 Positive Lymph Nodes Treated with or without Postmastectomy Radiation Therapy.

The use of postmastectomy radiation therapy (PMRT) has been recommended for patients with 4 or more positive lymph nodes, however, its role in patients with 1-3 positive lymph nodes remains unclear. The purpose of this study is to evaluate oncological outcomes for breast cancer patients with T1-2 tumors and 1-3 positive lymph nodes after undergoing PMRT. We performed a single-institution retrospective investigation that evaluated the association between PMRT and outcomes in breast cancer patients with T1-2 tumors and 1-3 positive lymph nodes, who underwent mastectomy from 2004 to 2015. Multivariable Cox proportional hazards regression was used to evaluate the association of PMRT with disease-free survival and overall survival. A total of 379 patients met inclusion criteria, of which 204 (54%) received PMRT while 175 (46%) did not receive PMRT following mastectomy and were followed over a median of 5.2 years (25th-75th percentile: 2.8-8.4 years). Recurrence was similar in patients receiving PMRT compared to those that did not: locoregional (0 vs 3, P = 0.061), distant (9 vs 3, P = 0.135) and any recurrence (11 vs 7, P = 0.525). After adjustment for potential confounding variables, PMRT was not associated with a statistically significant difference in disease-free survival (HR: 0.93; 95% CI: 0.48, 1.79) or overall survival (HR: 0.91; 95% CI: 0.45, 1.85). PMRT was not associated with improved oncological outcomes in patients with T1-2 breast cancer and 1-3 positive lymph nodes at our institution.

Surgeon Re-Excision Rates after Breast-Conserving Surgery: A Measure of Low-Value Care.

BACKGROUND: To better understand re-excision practice patterns after breast-conserving therapy (BCT), we evaluated variation in surgeon-specific re-excision rates and associated factors. STUDY DESIGN: We performed a retrospective analysis using Medicare claims from 2012 to 2018 to identify patients undergoing BCT and subsequent breast resection procedures within 12 months. We compared rates before and after the 2014 "no tumor on ink" consensus guideline. A hierarchical logistic regression model was also used to evaluate patient and physician characteristics associated with re-excision. RESULTS: We identified 291,065 female Medicare beneficiaries who underwent an initial BCT procedure, of which 19.0% had a re-excision. The overall re-excision rate was 22.1% in the pre-guideline period and 17.2% in the post-guideline period. For the 5,337 physicians that performed more than 10 initial BCT procedures during the study period, their physician-level re-excision rate ranged from 0% to 91.7% (median 18.2%). In total, 17.5% of the physicians had a re-excision rate greater than the expert consensus cutoff of 30%. The percentage of outlier physicians decreased from 22.2% in 2012 to 8.8% in 2017. High surgeon volume of BCT was associated with a lower re-excision odds (≥51 cases vs ≤20 cases: adjusted odds ratio 0.78; 95% CI 0.74 to 0.82; 21 to 50 cases vs ≤20 cases: adjusted odds ratio 0.92; 95% CI 0.88 to 0.96). Patient factors associated with decreased odds of re-excision were age older than 75 years and Northeast region of the US (adjusted odds ratio 0.93; 95% CI 0.89 to 0.98). CONCLUSIONS: Marked variation exists in surgeon re-excision rates among patients undergoing BCT, which might represent unnecessary operations for patients and a financial burden to the healthcare system. Formalizing a re-excision frequency metric could have implications for quality improvement and data-driven surgeon feedback aimed at reducing unwarranted variation.

Ductal Carcinoma In Situ.

Ductal carcinoma in situ has been stable in incidence for a decade and has an excellent prognosis. Breast conservation therapy is safe and effective for most patients. Adjuvant whole breast radiation therapy is recommended to reduce the risk of local recurrence. Accelerated partial breast irradiation is a promising alternative to decrease toxicity and improve cosmetic results. Adjuvant hormonal therapy can reduce local recurrence, but should be used cautiously. Future directions in management include developing predictive tools for guidance for use of adjuvant therapy and selecting low-risk patients with ductal carcinoma in situ in whom surgery may be safely omitted.

Tumor Site and Breast Cancer Prognosis.

INTRODUCTION: Various factors affect breast cancer prognosis; however, little information is available regarding the role of primary tumor site. The purpose of this study was to compare the survival and clinicopathologic characteristics of patients with breast cancer by primary tumor location. MATERIALS AND METHODS: We analyzed a prospectively collected single-institution breast cancer registry. Univariate and multivariable analyses were used to evaluate the association of tumor site with positive lymph node status, presence of metastasis, time to recurrence or death, and events of recurrence or death. Patients with tumors originating from the upper-outer quadrant were the reference group. RESULTS: From 2003 to 2015, 5295 patients with breast cancer were identified. Tumors originated from the upper-outer quadrant (36.2%), upper-inner quadrant (13.1%), lower-outer quadrant (9.8%), lower-inner quadrant (7.6%), nipple (1.2%), axillary tail (0.3%), or overlapping (24.7%). Tumors originated from overlapping lesions (odds ratio [OR], 1.58; 95% confidence interval [CI], 1.36-1.83) had higher odds of positive axillary lymph nodes, whereas tumors from the upper-inner (OR, 0.68; 95% CI, 0.56-0.84) and lower-inner quadrant (OR, 0.72; 95% CI, 0.56-0.93) had lower odds. Tumors from the lower-outer quadrant were associated with lower risk of death (hazard ratio, 0.64; 95% CI, 0.46-0.88), whereas tumors from overlapping lesions had higher risk (hazard ratio, 1.28; 95% CI, 1.05-1.55). CONCLUSION: The site of primary tumor may be an important characteristic affecting the prognosis of patients with breast cancer.

An interesting and unusual coronary artery anomaly.

Cardiac CT angiography utilized in the emergency room for triage of low-to-intermediate risk chest pain on occasion identifies unexpected abnormalities. In this case, multiple coronary anomalies existed in the same patient. Images and clinical decision making are discussed in this presentation. Coronary anomalies are being recognized with increased frequency due to increasing use of this modality in the evaluation of chest pain. The clinical implications of these findings are not always clear.

Transcatheter Aortic Valve Replacement: Current Technology and Future Directions.

Transcatheter aortic valve replacement as an alternative to open surgical repair is rapidly becoming more used in high-risk patients with aortic stenosis. Transcatheter aortic valve replacement offers the benefit of being much less invasive than traditional surgical repair and has evolved as a therapeutic option for patients with prohibitive surgical risk or those deemed surgically inoperable. Nevertheless, despite its potential to mitigate risk in this frail population, it comes with its own unique set of complications. Technological advancements in valve structure, function, and delivery have and continue to attempt to minimize these risks. This review aims to summarize current advancements in transcatheter aortic valve replacement technology while also introducing areas of future direction in this exciting new field.

Molecularly targeted agents and immunotherapy for the treatment of head and neck squamous cell cancer (HNSCC).

Squamous cell carcinoma is one of the most frequent tumors of the head and neck and often presents at an advanced-stage. Traditionally, treatment for head and neck squamous cell carcinoma (HNSCC) has included surgery, radiation, and chemotherapy depending on both the site and stage of disease. Although the treatment approach for local disease is often standardized, the management of recurrent and advanced disease is evolving. A better understanding of the molecular mechanisms of HNSCC has led to numerous promising investigations and the push for the development of novel therapies. Similarly, over the past several decades, growing data supports the notion that an individual's immune system can be manipulated in such a way to help eradicate cancer. The success of immunotherapeutic agents such as interleukin therapy and immune checkpoint inhibitor blockade in cancer, particularly advanced-stage melanoma, has stimulated researchers to uncover similar success stories in HNSCC. Examples of immunotherapeutics that are being studied for the treatment of HNSCC include adoptive T-cell therapy, vaccines, and immune checkpoint inhibitor proteins (e.g., anti-CTLA-4, -PD-1, -PD-L1). Molecularly targeted agents of interest include inhibitors of transmembrane growth factor receptors, angiogenesis, and PI3K/AKT/mTOR and NOTCH signaling pathways. To date, cetuximab, an epidermal growth factor receptor inhibitor, is the only targeted agent for HNSCC that was approved by the Federal Food and Drug Administration (FDA) on the basis that it improves overall survival when combined with chemotherapy or radiation. Herein, the authors provide an up-to-date review of immunotherapeutic and molecularly targeted agents for the treatment of HNSCC.

Transcatheter Aortic Valve Replacement Results in Improvement of Pulmonary Function in Patients With Severe Aortic Stenosis.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) has been identified as a risk factor for morbidity and mortality after transcatheter aortic valve replacement (TAVR). We hypothesized that a portion of pulmonary dysfunction in patients with severe aortic stenosis may be of cardiac origin, and has potential to improve after TAVR. METHODS: A retrospective analysis was made of consecutive TAVR patients from April 2008 to October 2014. Of patients who had pulmonary function testing and serum B-type natriuretic peptide data available before and after TAVR, 58 were found to have COPD (26 mild, 14 moderate, and 18 severe). Baseline variables and operative outcomes were explored along with changes in pulmonary function. Multiple regression analyses were performed to adjust for preoperative left ventricular ejection fraction and glomerular filtration rate. RESULTS: Comparison of pulmonary function testing before and after the procedure among all COPD categories showed a 10% improvement in forced vital capacity (95% confidence interval: 4% to 17%) and a 12% improvement in forced expiratory volume in 1 second (95% confidence interval: 6% to 19%). There was a 29% decrease in B-type natriuretic peptide after TAVR (95% confidence interval: -40% to -16%). An improvement of at least one COPD severity category was observed in 27% of patients with mild COPD, 64% of patients with moderate COPD, and 50% of patients with severe COPD. There was no 30-day mortality in any patient group. CONCLUSIONS: In patients with severe aortic stenosis, TAVR is associated with a significant improvement of pulmonary function and B-type natriuretic peptide. After TAVR, the reduction in COPD severity was most evident in patients with moderate and severe pulmonary dysfunction.

Effects of blocking developmental cell death on sexually dimorphic calbindin cell groups in the preoptic area and bed nucleus of the stria terminalis.

BACKGROUND: Calbindin-D28 has been used as a marker for the sexually dimorphic nucleus of the preoptic area (SDN-POA). Males have a distinct cluster of calbindin-immunoreactive (ir) cells in the medial preoptic area (CALB-SDN) that is reduced or absent in females. However, it is not clear whether the sex difference is due to the absolute number of calbindin-ir cells or to cell position (that is, spread), and the cellular mechanisms underlying the sex difference are not known. We examined the number of cells in the CALB-SDN and surrounding regions of C57Bl/6 mice and used mice lacking the pro-death gene, Bax, to test the hypothesis that observed sex differences are due to cell death. METHODS: Experiment 1 compared the number of cells in the CALB-SDN and surrounding regions in adult males, females, and females injected with estradiol benzoate on the day of birth. In experiment 2, cell number in the CALB-SDN and adjacent regions were compared in wild-type and Bax knockout mice of both sexes. In addition, calbindin-ir cells were quantified within the principal nucleus of the bed nucleus of the stria terminalis (BNSTp), a nearby region that is larger in males due to Bax-dependent cell death. RESULTS: Males had more cells in the CALB-SDN as well as in surrounding regions than did females, and estradiol treatment of females at birth masculinized both measures. Bax deletion had no effect on cell number in the CALB-SDN or surrounding regions but increased calbindin-ir cell number in the BNSTp. CONCLUSIONS: The sex difference in the CALB-SDN of mice results from an estrogen-dependent difference in cell number with no evidence found for greater spread of cells in females. Blocking Bax-dependent cell death does not prevent sex differences in calbindin-ir cell number in the BNST or CALB-SDN but increases calbindin-ir cell number in the BNSTp of both sexes.

In vivo expression of polyglutamine-expanded huntingtin by mouse striatal astrocytes impairs glutamate transport: a correlation with Huntington's disease subjects.

Huntington's disease (HD) is a neurodegenerative disorder previously thought to be of primary neuronal origin, despite ubiquitous expression of mutant huntingtin (mHtt). We tested the hypothesis that mHtt expressed in astrocytes may contribute to the pathogenesis of HD. To better understand the contribution of astrocytes in HD in vivo, we developed a novel mouse model using lentiviral vectors that results in selective expression of mHtt into striatal astrocytes. Astrocytes expressing mHtt developed a progressive phenotype of reactive astrocytes that was characterized by a marked decreased expression of both glutamate transporters, GLAST and GLT-1, and of glutamate uptake. These effects were associated with neuronal dysfunction, as observed by a reduction in DARPP-32 and NR2B expression. Parallel studies in brain samples from HD subjects revealed early glial fibrillary acidic protein expression in striatal astrocytes from Grade 0 HD cases. Astrogliosis was associated with morphological changes that increased with severity of disease, from Grades 0 through 4 and was more prominent in the putamen. Combined immunofluorescence showed co-localization of mHtt in astrocytes in all striatal HD specimens, inclusive of Grade 0 HD. Consistent with the findings from experimental mice, there was a significant grade-dependent decrease in striatal GLT-1 expression from HD subjects. These findings suggest that the presence of mHtt in astrocytes alters glial glutamate transport capacity early in the disease process and may contribute to HD pathogenesis.

Talking to patients about risk.

Doctors talking with patients about alternative treatments for life-threatening disease must be sensitive to the ways in which patients understand and deal with risk. Risk is a combination of chance, measured by some known or estimated probability, and loss, which is a function of magnitude and the subjective value placed upon it by the person at risk. Prospect theory, economics, and the financial model of risk management provide insights that can help doctors as they present the best available data on the probable outcomes of various treatments and then guide patients through their own assessment of their preferences regarding those outcomes.