Society of Surgical Oncology Breast Disease Site Working Group Statement on Contralateral Mastectomy: Indications, Outcomes, and Risks.

Rates of contralateral mastectomy (CM) among patients with unilateral breast cancer have been increasing in the United States. In this Society of Surgical Oncology position statement, we review the literature addressing the indications, risks, and benefits of CM since the society's 2017 statement. We held a virtual meeting to outline key topics and then conducted a literature search using PubMed to identify relevant articles. We reviewed the articles and made recommendations based on group consensus. Patients consider CM for many reasons, including concerns regarding the risk of contralateral breast cancer (CBC), desire for improved cosmesis and symmetry, and preferences to avoid ongoing screening, whereas surgeons primarily consider CBC risk when making a recommendation for CM. For patients with a high risk of CBC, CM reduces the risk of new breast cancer, however it is not known to convey an overall survival benefit. Studies evaluating patient satisfaction with CM and reconstruction have yielded mixed results. Imaging with mammography within 12 months before CM is recommended, but routine preoperative breast magnetic resonance imaging is not; there is also no evidence to support routine postmastectomy imaging surveillance. Because the likelihood of identifying an occult malignancy during CM is low, routine sentinel lymph node surgery is not recommended. Data on the rates of postoperative complications are conflicting, and such complications may not be directly related to CM. Adjuvant therapy delays due to complications have not been reported. Surgeons can reduce CM rates by encouraging shared decision making and informed discussions incorporating patient preferences.

Unexpected Single-Ligand Occupancy and Negative Cooperativity in the SARS-CoV-2 Main Protease.

Many homodimeric enzymes tune their functions by exploiting either negative or positive cooperativity between subunits. In the SARS-CoV-2 Main protease (Mpro) homodimer, the latter has been suggested by symmetry in most of the 500 reported protease/ligand complex structures solved by macromolecular crystallography (MX). Here we apply the latter to both covalent and noncovalent ligands in complex with Mpro. Strikingly, our experiments show that the occupation of both active sites of the dimer originates from an excess of ligands. Indeed, cocrystals obtained using a 1:1 ligand/protomer stoichiometry lead to single occupation only. The empty binding site exhibits a catalytically inactive geometry in solution, as suggested by molecular dynamics simulations. Thus, Mpro operates through negative cooperativity with the asymmetric activity of the catalytic sites. This allows it to function with a wide range of substrate concentrations, making it resistant to saturation and potentially difficult to shut down, all properties advantageous for the virus' adaptability and resistance.

Deciphering the free energy landscapes of SARS-CoV-2 wild type and Omicron variant interacting with human ACE2.

The binding of the receptor binding domain (RBD) of the SARS-CoV-2 spike protein to the host cell receptor angiotensin-converting enzyme 2 (ACE2) is the first step in human viral infection. Therefore, understanding the mechanism of interaction between RBD and ACE2 at the molecular level is critical for the prevention of COVID-19, as more variants of concern, such as Omicron, appear. Recently, atomic force microscopy has been applied to characterize the free energy landscape of the RBD-ACE2 complex, including estimation of the distance between the transition state and the bound state, xu. Here, using a coarse-grained model and replica-exchange umbrella sampling, we studied the free energy landscape of both the wild type and Omicron subvariants BA.1 and XBB.1.5 interacting with ACE2. In agreement with experiment, we find that the wild type and Omicron subvariants have similar xu values, but Omicron binds ACE2 more strongly than the wild type, having a lower dissociation constant KD.

Innovation in Breast Surgery: Practical and Ethical Considerations.

The adoption of innovation is essential to the evolution of patient care. Breast surgical oncology advances through incorporating new techniques, devices, and procedures. Historical changes in practice standards from radical to modified radical mastectomy or axillary node dissection to sentinel node biopsy reduced morbidity without sacrifice in oncologic outcome. Contemporary oncoplastic techniques afford broader consideration for breast conservation and the potential for improved cosmetic outcomes. At present, many breast surgeons face the decision of which wireless device to use for localization of nonpalpable lesions. Consideration for future changes, such as robotic mastectomy, are on the horizon. No guideline exists to assist breast surgeons in the adoption of innovation into practice. The Ethics Committee of the American Society of Breast Surgeons acknowledges that breast surgeons confront many questions associated with onboarding innovation. This paper aims to provide a framework for asking relevant questions along with the ethical principles to consider when integrating an innovation into practice.

Genetic Characterization of African Swine Fever Virus in Various Outbreaks in Central and Southern Vietnam During 2019-2021.

This study aimed to identify potential genetic diversity among African swine fever virus (ASFV) strains circulating in central and southern Vietnam. Thirty ASFV strains were collected from domestic pigs and convalescent pigs with ASFV-infected clinical signs from 19 different provinces of central and southern Vietnam during 2019-2021. A portion of the B646L (p72) gene and the entire E183L (p54), CP204L (p30), and B602L (CVR) genes were amplified, purified, and sequenced. Web-based BLAST and MEGA X software were used for sequence analysis. Analysis of the partial B646L (p72) gene, the full-length E183L (p54) and CP204L (p30) genes, and the central hypervariable region (CVR) of the B602L gene sequence showed that all 30 ASFV isolates belonged to genotype II and were 100% identical to the previously identified strains in Vietnam and China. Analysis of the p72, p54, and p30 regions did not indicate any change in the nucleotide and amino acid sequences among these strains in 3 years of research. No novel variant was found in the CVR within the B602L gene. Analysis of the CVR showed that these ASFV strains belong to subgroup XXXII. The results of this study revealed that these ASFVs shared high similarity with ASFV isolates detected previously in northern Vietnam and China. Taken together, the results of this study and a previous study in Vietnam showed high stability and no genetic diversity in the ASFV genome.

Impact of the COVID-19 Pandemic on Cancer Clinical Trials.

The COVID-19 pandemic has had widespread impact on healthcare, resulting in modifications to how we perform cancer research, including clinical trials for cancer. The impact of some healthcare workers and study coordinators working remotely and patients minimizing visits to medical facilities impacted clinical trial participation. Clinical trial accrual dropped at the onset of the pandemic, with improvement over time. Adjustments were made to some trial protocols, allowing telephone or video-enabled consent. Certain study activities were permitted to be performed by local healthcare providers or at local laboratories to maximize patients' ability to continue on study during these challenging times. We discuss the impact of COVID-19 on cancer clinical trials and changes at the local, cooperative group, and national level.

The Interplay of Cholesterol and Ligand Binding in hTSPO from Classical Molecular Dynamics Simulations.

The translocator protein (TSPO) is a 18kDa transmembrane protein, ubiquitously present in human mitochondria. It is overexpressed in tumor cells and at the sites of neuroinflammation, thus representing an important biomarker, as well as a promising drug target. In mammalian TSPO, there are cholesterol-binding motifs, as well as a binding cavity able to accommodate different chemical compounds. Given the lack of structural information for the human protein, we built a model of human (h) TSPO in the apo state and in complex with PK11195, a molecule routinely used in positron emission tomography (PET) for imaging of neuroinflammatory sites. To better understand the interactions of PK11195 and cholesterol with this pharmacologically relevant protein, we ran molecular dynamics simulations of the apo and holo proteins embedded in a model membrane. We found that: (i) PK11195 stabilizes hTSPO structural fold; (ii) PK11195 might enter in the binding site through transmembrane helices I and II of hTSPO; (iii) PK11195 reduces the frequency of cholesterol binding to the lower, N-terminal part of hTSPO in the inner membrane leaflet, while this impact is less pronounced for the upper, C-terminal part in the outer membrane leaflet, where the ligand binding site is located; (iv) very interestingly, cholesterol most frequently binds simultaneously to the so-called CRAC and CARC regions in TM V in the free form (residues L150-X-Y152-X(3)-R156 and R135-X(2)-Y138-X(2)-L141, respectively). However, when the protein is in complex with PK11195, cholesterol binds equally frequently to the CRAC-resembling motif that we observed in TM I (residues L17-X(2)-F20-X(3)-R24) and to CRAC in TM V. We expect that the CRAC-like motif in TM I will be of interest in future experimental investigations. Thus, our MD simulations provide insight into the structural features of hTSPO and the previously unknown interplay between PK11195 and cholesterol interactions with this pharmacologically relevant protein.

Overcharging of the Zinc Ion in the Structure of the Zinc-Finger Protein Is Needed for DNA Binding Stability.

Zinc-finger structure, in which a Zn2+ ion binds to four cysteines or histidines in a tetrahedral structure, is a very common motif of nucleic acid-binding proteins. The corresponding interaction model is present in 3% of the genes in the human genome. As a result, the zinc finger has been extremely useful in various therapeutic and research capacities and in biotechnology. In a stable configuration of the zinc finger, the cysteine amino acids are deprotonated and become negatively charged. Thus, the Zn2+ ion is overscreened by four cysteine charges (overcharged). Whether this overcharged configuration is also stable when such a negatively charged zinc finger binds to a negatively charged DNA molecule is unknown. We investigated how the deprotonated state of cysteine influences its structure, dynamics, and function in binding to DNA molecules by using an all-atom molecular dynamics simulation up to the microsecond range of an androgen receptor protein dimer. Our results showed that the deprotonated state of cysteine residues is essential for the mechanical stabilization of the functional, folded conformation. This state stabilizes not only the protein structure but also the protein-DNA binding complex. The differences in the structural and energetic properties of the two sequence-identical monomers are also investigated and show the strong influence of DNA on the structure of the zinc-finger protein dimer upon complexation. Our result can potentially lead to a better molecular understanding of one of the most common classes of zinc fingers.

Chicken albumen-based whispering gallery mode microlasers.

Microlasers based on biomaterials have attracted enormous interest because of their promising potential for future applications in medical treatments, bio-tracking, and biosensing. In this work, we demonstrate chicken albumen as a novel and excellent low-cost biomaterial for a laser cavity. By using a simple but effective emulsion process, rhodamine B-doped chicken albumen microspheres with various diameters ranging from 20 µm to 100 µm can be fabricated. Under optical pulse excitation, these microspheres emit lasing emission. The lasing mechanism is investigated and ascribed to the whispering gallery mode (WGM). A threshold of 23.2 µJ mm-2 and a high Q-factor of approximately 2400 are obtained from an 82 µm-diameter microsphere. Size-dependent lasing characteristics are also examined, and the result shows good agreement with the WGM theory. Interestingly, these microsphere biolasers can operate in aqueous and biological environments such as water and human blood serum, which makes them a promising candidate for laser-based biosensing and biological applications.

Molecular mechanism of ultrasound interaction with a blood brain barrier model.

The brain is strictly protected by the blood brain barrier preventing the crossing of therapeutics to treat brain diseases. The high and low intensity focused ultrasound methods have been used to temporarily open the blood brain barrier, facilitating the transport of drugs. The methods are very promising because the opening is transient, localized, and noninvasive. However, the molecular mechanism of the opening is unknown, and this limits the development and application of these methods. With this in mind, we carry out a molecular dynamics simulation study to understand the interaction of ultrasound with the cell membrane and the tight junction. Our minimal blood brain barrier model is composed of two lipid bilayers, mimicking two portions of neighboring cells, connected together by a tight junction formed by a pair of two cis-dimers of the claudin-5 protein. Using an experimental ultrasound frequency of 50 MHz, simulations show that at low intensities, ultrasound does not impact the structure of the cell membranes and tight junction, implying that the direct interaction of ultrasound with the blood brain barrier is not responsible for the experimentally observed opening. At high intensities, the ultrasound pulls the monolayers of individual cell membrane lipid bilayers apart, creating air compartments inside the bilayers. This reduces the free energy barrier for the translocation of drugs across the lipid bilayer and enhances drug permeability. At very high intensities, the two monolayers are largely separated, resulting in cell damage and implying that the blood brain barrier is primarily opened at the experimentally observed damaged areas.

Decreasing Use of Axillary Dissection in Node-Positive Breast Cancer Patients Treated with Neoadjuvant Chemotherapy.

BACKGROUND: Neoadjuvant chemotherapy (NAC) may downstage axillary disease in node-positive breast cancer. Several clinical trials have shown that sentinel lymph node (SLN) surgery after NAC is feasible for these patients. We sought to evaluate the use of SLN surgery and ALND in cN1 patients undergoing NAC. METHODS: We identified all patients with biopsy-proven cN1 breast cancer treated with NAC at our institution between January 2009 and December 2017. Approximated biologic subtype was determined by estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) status. Cochran-Armitage trend and Chi square tests were used for statistical analysis. RESULTS: Of 430 cN1 patients treated with NAC, 93 (22%) underwent SLN surgery only, 100 (23%) underwent SLN and ALND, and 237 (55%) underwent ALND only. The use of SLN surgery (± ALND) increased from 28% in 2009 to 86% in 2017 (p < 0.001), while the performance of ALND decreased from 100% in 2009 to 38% in 2017 (p < 0.001). Among SLN+ patients who underwent ALND, disease was limited to the SLNs in 25/73 (34%) patients. The nodal pathologic complete response rate was 46% and varied by tumor subtype (p < 0.001). Among patients undergoing SLN surgery, ALND was avoided in 48% of patients overall and varied by biologic subtype: 55% ER-/HER2+, 61% ER+/HER2+, 62% ER-/HER2-, and 31% ER+/HER2- (p = 0.001). With short-term follow-up, no nodal recurrences have occurred in patients without ALND. CONCLUSIONS: We observed a significant shift in axillary surgery for cN1 breast cancer patients treated with NAC, with increasing use of SLN surgery to assess nodal treatment response, and decreasing use of ALND.

Ethical Considerations of Medical Photography in the Management of Breast Disease.

BACKGROUND: Medical photography has become an important component of the evaluation and management of patients across many specialties. It is increasingly utilized in contemporary practice with modern smartphones and enhanced digital media. Photography can enhance and improve treatment plans and communication between providers and patients. Additionally, photography supplements education, research, and marketing in both print and social media. Ethical and medicolegal standards for medical photography, specifically for patients with breast disease, have not been formally developed to guide medical providers. PURPOSE: To provide guidelines for breast care physicians using medical photography, the Ethics Committee of the American Society of Breast Surgeons presents an updated review of the literature and recommendations for ethical and practical use of photography in patient care. METHODS: An extensive PubMed review of articles in English was performed to identify studies and articles published prior to 2018 investigating the use of medical photography in patient care and the ethics of medical photography. After review of the literature, members of the Ethics Committee convened a panel discussion to identify best practices for the use of medical photography in the breast care setting. Results of the literature and panel discussion were then incorporated to provide the content of this article. CONCLUSION: The Ethics Committee of the American Society of Breast Surgeons acknowledges that photography of the breast has become an invaluable tool in the delivery of state-of-the-art care to our patients with breast disease, and we encourage the use of this important medium. Physicians must be well informed regarding the concerns associated with medical photography of the breast to optimize its safe and ethical use in clinical practice.

Localizing the Clipped Node in Patients with Node-Positive Breast Cancer Treated with Neoadjuvant Chemotherapy: Early Learning Experience and Challenges.

BACKGROUND: Placement of a clip in the positive node in patients presenting with node-positive breast cancer treated with neoadjuvant chemotherapy (NAC) allows resection of the clipped node at SLN surgery and improves the accuracy of surgical staging. We sought to evaluate our experience with SLN surgery with resection of the clipped node since incorporation into our practice. METHODS: With Institutional Review Board approval, we evaluated all breast cancer patients with a percutaneous biopsy-positive axillary lymph node, clipped at the time of diagnosis, who underwent NAC followed by surgery. RESULTS: Fifty-six node-positive patients were identified. Eighteen patients (32.1%) underwent axillary dissection without sentinel lymph node (SLN) surgery, and 38 patients underwent SLN surgery (18 patients underwent SLN surgery alone, and 20 patients underwent SLN surgery and axillary lymph node dissection). In 25 patients, preoperative localization of the clipped node with an 125I radioactive seed was attempted. This was performed by ultrasound guidance in 18 cases (72%), computed tomography (CT) guidance in two cases (8%), and was unable to be localized in five cases (20%). In all 20 seed-localized cases, the seed and the clipped node were resected along with additional SLNs. In 14 patients without seed localization (nine not attempted, five unable to be localized), the clipped node was resected in 11 cases (79%)-as one of the SLNs (6), by intraoperative ultrasound (4), or by palpation (1). Overall, the clipped node was resected in 31/34 (91%) cases. CONCLUSION: Preoperative ultrasound localization of the clipped node was successful in 72% of cases. Alternatively, the clipped node can be identified by preoperative CT, routine SLN surgery, intraoperative ultrasound, or palpation.

Factors Influencing Use of Hormone Therapy for Ductal Carcinoma In Situ: A National Cancer Database Study.

BACKGROUND: Adjuvant hormonal therapy (HT) reduces breast cancer recurrence risk in estrogen receptor-positive (ER+) ductal carcinoma in situ (DCIS). We assessed national practice patterns and influence of surgery and pathology on HT use in DCIS. METHODS: Data on DCIS patients diagnosed from 2004 to 2014 were extracted from the National Cancer Database, and patients were classified according to ER status and whether HT was received. Factors associated with HT use were assessed using Chi square tests for univariate analysis and logistic regression for multivariate analysis. RESULTS: Overall, 207,738 patients were evaluable as follows: ER+ (69.3%), ER- (13.7%), and ER unknown (17.0%). Among ER+ DCIS patients, 46.5% received HT, and HT use increased over time (42.3% in 2004 to 50.6% in 2014; p < 0.001). In contrast, 7.8% of ER- DCIS patients received HT, decreasing from 10.7% in 2004 to 5.9% in 2014 (p < 0.001). HT use varied by surgery type (BCS, 53.9%; unilateral mastectomy, 31.5%; and bilateral mastectomy, 8.1%; p < 0.001) and use was higher in BCS patients receiving adjuvant radiation than those not receiving radiation (62.7 vs. 29.1%; p < 0.001). Males treated with BCS were less likely to receive HT than females (43.2 vs. 54.0%; p < 0.001). In the BCS subset, higher use of HT was associated with more recent calendar year, age between 40 and 80 years, female sex, positive progesterone receptor status, and radiation use. CONCLUSION: Adjuvant HT use in ER+ DCIS has increased over time, with the highest rates in patients treated with BCS and radiation. While inappropriate HT use was observed in ER- and bilateral mastectomy patients, the frequency of use in these categories decreased over time.

Breast Cancer-Related Lymphedema Risk is Related to Multidisciplinary Treatment and Not Surgery Alone: Results from a Large Cohort Study.

BACKGROUND: Breast cancer-related lymphedema (BCRL) is a significant complication for women undergoing treatment. We assessed BCRL incidence and risk factors in a large population-based cohort. METHODS: We utilized the Olmsted County Rochester Epidemiology Project Breast Cancer Cohort from 1990-2010 and ascertained BCRL and risk factors. The cumulative incidence estimator was used to estimate the rate of BCRL; competing risks regression was used for multivariable analysis. RESULTS: A total of 1794 patients with stage 0-3 breast cancer with a median of 10 years follow-up were included. The cumulative incidence of BCRL diagnosis within 5 years was 9.1% [95% confidence interval (CI) 7.8-10.5%]. No BCRL events occurred among patients without axillary surgery. In the axillary surgery subset (n = 1512), the 5-year incidence of BCRL was 5.3% in sentinel lymph node (SLN) surgery and 15.9% in axillary dissection (ALND) patients (p < 0.001). In patients treated with surgery only, BCRL rates were not different between ALND versus SLN (3.5 and 4.1% at 5 years, p = 0.36). Addition of breast or chest wall radiation more than doubled the BCRL rate in ALND patients (3.5 vs. 9.5% at 5 years, p = 0.01). The groups with highest risk (>25% at 5 years) all involved ALND with nodal RT and/or anthracycline/cytoxan + taxane chemotherapy. In multivariable analysis of patients with any axillary surgery factors significantly associated with BCRL were ALND, chemotherapy, radiation, and obesity. CONCLUSIONS: BCRL is a sequelae of multimodal breast cancer treatment and risk is multifactorial. BCRL rates are higher in patients receiving chemotherapy, radiation, ALND, more advanced disease stage, and higher body mass index.

Identifying a subset of patients with DCIS who have a low likelihood of residual disease at surgical excision following a core needle biopsy.

BACKGROUND AND OBJECTIVES: Current randomized controlled trials are investigating the outcomes of non-surgical treatment for patients with ductal carcinoma in situ (DCIS). We sought to evaluate pre-operative factors associated with no residual disease at definitive resection following a core needle biopsy (CNB) diagnosis of DCIS. METHODS: Eight hundred and thirty-four operations for DCIS were performed at our institution between January 2004 and October 2014. We evaluated patient and biopsy tumor characteristics to determine pre-operative factors associated with no residual disease at surgical resection using uni- and multivariable analyses. RESULTS: Sixty-nine patients (8%) had no residual disease on final pathology. On multivariable analysis, low- or intermediate-grade lesions, <1 cm in size on mammography, and lesions where ≥90% of calcifications were removed correlated with finding no residual disease on final pathology, c-statistic 0.84. Of the 14 patients with all three low-risk factors, 36% had no residual disease on final pathology. CONCLUSIONS: Although our multivariable analysis performed well, its clinical utility would be limited as we were unable to identify a subset of patients with DCIS in whom the probability of finding no residual disease is low enough to consider routine use of non-surgical management.

DNA like-charge attraction and overcharging by divalent counterions in the presence of divalent co-ions.

Strongly correlated electrostatics of DNA systems has drawn the interest of many groups, especially the condensation and overcharging of DNA by multivalent counterions. By adding counterions of different valencies and shapes, one can enhance or reduce DNA overcharging. In this paper, we focus on the effect of multivalent co-ions, specifically divalent co-ions such as SO[Formula: see text]. A computational experiment of DNA condensation using Monte Carlo simulation in grand canonical ensemble is carried out where the DNA system is in equilibrium with a bulk solution containing a mixture of salt of different valency of co-ions. Compared to systems with purely monovalent co-ions, the influence of divalent co-ions shows up in multiple aspects. Divalent co-ions lead to an increase of monovalent salt in the DNA condensate. Because monovalent salts mostly participate in linear screening of electrostatic interactions in the system, more monovalent salt molecules enter the condensate leads to screening out of short-range DNA-DNA like charge attraction and weaker DNA condensation free energy. The overcharging of DNA by multivalent counterions is also reduced in the presence of divalent co-ions. Strong repulsions between DNA and divalent co-ions and among divalent co-ions themselves lead to a depletion of negative ions near the DNA surface as compared to the case without divalent co-ions. At large distances, the DNA-DNA repulsive interaction is stronger in the presence of divalent co-ions, suggesting that divalent co-ions' role is not only that of simple stronger linear screening.

Grand-canonical simulation of DNA condensation with two salts, effect of divalent counterion size.

The problem of DNA- DNA interaction mediated by divalent counterions is studied using a generalized grand-canonical Monte-Carlo simulation for a system of two salts. The effect of the divalent counterion size on the condensation behavior of the DNA bundle is investigated. Experimentally, it is known that multivalent counterions have strong effect on the DNA condensation phenomenon. While tri- and tetra-valent counterions are shown to easily condense free DNA molecules in solution into toroidal bundles, the situation with divalent counterions is not as clear cut. Some divalent counterions like Mg(+2) are not able to condense free DNA molecules in solution, while some like Mn(+2) can condense them into disorder bundles. In restricted environment such as in two dimensional system or inside viral capsid, Mg(+2) can have strong effect and able to condense them, but the condensation varies qualitatively with different system, different coions. It has been suggested that divalent counterions can induce attraction between DNA molecules but the strength of the attraction is not strong enough to condense free DNA in solution. However, if the configuration entropy of DNA is restricted, these attractions are enough to cause appreciable effects. The variations among different divalent salts might be due to the hydration effect of the divalent counterions. In this paper, we try to understand this variation using a very simple parameter, the size of the divalent counterions. We investigate how divalent counterions with different sizes can lead to varying qualitative behavior of DNA condensation in restricted environments. Additionally, a grand canonical Monte-Carlo method for simulation of systems with two different salts is presented in detail.