Development and Prospective Validation of a Risk Calculator That Predicts a Low Risk Cohort for Atypical Ductal Hyperplasia Upstaging to Malignancy: Evidence for a Watch and Wait Strategy of a High-Risk Lesion.

BACKGROUND: Guidelines recommend surgical excision of atypical ductal hyperplasia (ADH) due to the concern of undersampling a potential malignancy on core needle biopsy (CNB). The purpose of this study was to determine clinical, radiological and pathological variables associated with ADH upstaging to cancer and to develop a predictive risk calculator capable of identifying women who have a low oncological risk of upstaging. METHODS: A prospectively collected database from a tertiary breast referral center was analyzed for women diagnosed with ADH on CNB between January 2013 to December 2017 who underwent surgical excision. CNB and surgical pathology reports were examined to determine rate of upstaging. The association between clinical, radiological and pathological variables were evaluated using regression analysis to determine predictors of ADH upstaging to cancer. Significant variables (p ≤ 0.05) identified on univariate analysis were assigned a score of "1" and were included in the ADH upstaging risk calculator. RESULTS: A total of 1986 patients underwent surgery for a high-risk lesion. We identified 318 (16.0%) patients who had ADH identified on their CNB who underwent surgery-of which 290 were included in our study. The upstage rate was 24.8%. Five variables were associated with upstaging and included in our calculator: (1) lesion > 5 mm on ultrasound; (2) lesion > 5 mm on mammogram; (3) one or more "high-risk" lesion(s) on CNB; (4) pathological suspicion for cancer and; (5) incomplete removal of calcifications on CNB. Patients with a score of 0 had a 2% risk of being upstaged to cancer and were deemed low risk with 17.2% of patients falling within this category. CONCLUSIONS: Patients with ADH on CNB can be stratified into a low oncological cohort who have a 2% risk of being upstaged to carcinoma. In the future, these select patients may be counselled and potentially offered observation as an alternative to surgery.

Is microductectomy still necessary to diagnose breast cancer: a 10-year study on the effectiveness of duct excision and galactography.

PURPOSE: Patients with spontaneous nipple discharge (SND) who have neither clinically palpable masses nor evidence of disease on imaging with mammogram and/or ultrasound are traditionally investigated with galactogram and duct excision. As breast imaging improves, it has raised the question whether galactography and microductectomy are necessary to diagnose breast cancer. The purpose of this study was to determine the incidence of malignancy in patients presenting with SND who underwent microductectomy and to evaluate the utility of duct excision and galactography in patients whose initial clinical and radiological evaluation were negative. METHODS: A 10-year retrospective study was conducted in British Columbia's largest tertiary breast referral center examining the clinical, radiological and pathological results for all patients who underwent a microductectomy procedure for SND between 2008 and 2017. RESULTS: A total of 231 microductectomies were performed and the overall incidence of malignancy was 13% (n = 32). Following initial work up, 155 patients (67%) had only discharge on exam and no radiologically suspicious findings of malignant disease. Of these patients, 14% (n = 21) were diagnosed with cancer by duct excision. Galactography yielded a sensitivity and specificity of 63% and 36%, respectively (PPV 15% and NPV 85%). Lastly, we found that 3% of patients (n = 8) initially diagnosed with benign disease later developed breast cancer. CONCLUSIONS: Patients with SND should continue to be evaluated with microductectomy to prevent missing a breast cancer. Moreover, we do not recommend performing galactography for diagnosing breast cancer due to poor sensitivity and specificity though it may assist in preoperative planning.

Incorporating Lymphovenous Anastomosis in Clinically Node-Positive Women Receiving Neoadjuvant Chemotherapy: A Shared Decision-Making Model and Nuanced Approached to the Axilla.

INTRODUCTION: Lymphedema remains a risk for 13-34% of breast cancer patients who require an axillary dissection (ALND) and radiation. Immediate lymphovenous anastomosis (LVA) may mitigate lymphedema by up to 30% by restoring the physiologic lymphatic drainage immediately after ALND. Currently, completion of ALND (cALND) versus radiation after neoadjuvant therapy (NAC) is being addressed by the Alliance A11202 trial, leaving a paucity of data to guide practice. Our study describes the implementation process of LVA into clinical practice after NAC for node-positive breast cancer in the current clinical context. METHODS: We reviewed a prospective database of LVA in node-positive patients (cT1-4,Nany) who received NAC followed by axillary surgery ± immediate LVA from October 2021 to 2022. The evolution of the surgical approach is described. Specifically, patients who downstaged to clinically negative nodes post-NAC were offered targeted SLNB with dual-tracer and intraoperative frozen section (FS). Patients were reminded that the standard of care for any node positive is cALND. Immediate cALND with LVA was performed for grossly positive nodes or all positive SLNs; cALND was omitted for those with negative SLNs. For a microscopic disease on a frozen section, a shared decision was made pre-operatively, given each patient's differing valuations of the benefit and risks of cALND ± LVA versus no cALND with planned regional radiation postoperatively. LVA was offered as an option as part of our institutional evaluation of the procedure. RESULTS: A total of 15 patients were included; the mean age was 49.9 (range 32-75) with stage IIA to IIIB breast cancer. Of these, 6 (40%) were triple negative, 5 (33.3%) HER-2 positive, and 4 (26.7%) ER/PR+ HER-2 negative. There were 13 women (86.7%) who had persistent axillary adenopathy based on clinical and/or ultrasound assessment, with 8 patients proceeding directly to ALND with LVA. Among these patients, 3 (37.5%) had pathologic nodal disease, and 5 (62.5%) were node negative, confirming the limitations of pre-operative imaging. As a result, the subsequent 7 (46.7%) underwent targeted SLNB with FS, with 3 patients (42.9%) avoiding an ALND as a result of a negative FS. A total of 4 patients (57.1%) had 1 or more positive lymph nodes on FS: 3 proceeded with a cALND and LVA, and 1 patient (14.2%) opted for no cALND based on a pre-operative discussion and received adjuvant radiation and chemotherapy. Of the 11 patients who underwent ALND and LVA, 1 patient (9.1%) developed lymphedema at 6.9 months following their surgery. The accuracy, sensitivity, and specificity of pre-operative US were 46.7%, 85.7%, and 12.5% and intraoperative FS were 88.0%, 72.7%, and 100%, respectively. CONCLUSIONS: As adjuvant nodal radiation and systemic therapy continue to improve, the benefit of a cALND in patients with the limited residual disease remains unclear as we await the outcomes from clinical trials. In the era of clinical uncertainty, we propose a nuanced approach to the axilla by utilizing a shared decision model with patients, incorporating targeted SLNB with FS and completion node dissection when required and desired by the patient, coupled with LVA in a simple stepwise treatment pathway.

Mutation of conserved tryptophan residues at the dimer interface of Staphylococcus aureus nitric oxide synthase.

Nitric oxide synthases (NOSs) share two invariant tryptophan residues within a conserved helical lariat that is part of the pterin-binding site and dimer interface. We mutated Staphylococcus aureus NOS Trp-314 (to alanine, phenylalanine, tyrosine and histidine) and Trp-316 (to alanine, phenylalanine and tyrosine) and characterized the effects of mutation on heme environment, quaternary structure, enzymatic activity, and substrate affinity. With arginine present, all saNOS variants bound heme with native thiolate ligation, formed high spin ferric complexes and were dimeric. All variants catalyze the peroxide-dependent oxidation of N-hydroxy-l-arginine, at rates from 10% to 55% of wild type activity. Arginine-free proteins are dimeric with the exception of W314A. Arginine affinity for all variants decreases with increasing temperature between 15 and 42 °C but is precipitous for position-314 variants. Previous structural and biophysical characterization of NOS oxygenase domains demonstrated that the protein can exist in either a tight or loose conformation, with the former corresponding to the active state of the protein. In the position-314 variants it is likely that the loose conformation is favoured, owing to the loss of a hydrogen bond between the indole side chain and the polypeptide backbone of the helical lariat.

Implementation and validation of a risk stratification method at The Ottawa Hospital to guide thromboprophylaxis in ambulatory cancer patients at intermediate-high risk for venous thrombosis.

BACKGROUND: Cancer patients have a significantly higher risk of developing a venous thromboembolism (VTE) compared to non-cancer patients and yet studies suggest VTE risk among ambulatory cancer patients varies widely. Recently, predictive models capable of risk-stratifying a broad range of ambulatory cancer outpatients have been developed. Using the Khorana model a score of 2 was intermediate-high risk for VTE as reported by Ay and colleagues. However, validation in a broader population and methods to implement this model seamlessly into clinical practice are lacking. OBJECTIVE: To create and assess the feasibility of an innovative computerized Care Process Management System (CPMS) that would automatically access electronic medical records to calculate in real-time the risk of VTE in patients with active cancer using an established VTE risk scoring system. METHODS: A prospective observational study of all newly referred cancer patients at the Ottawa Regional Cancer Center, the sole cancer care provider for 1.2 million inhabitants, was conducted. RESULTS: 699 new referrals were determined to have a cancer diagnosis for the first time as identified by the computer software and qualified for our study and 580 were eligible. In total 25% had intermediate-high risk for VTE and during the 3-month follow up period, 16 of the 143 (11%) developed a VTE which further validates the Khorana model for identifying intermediate-high risk patients. Of the 437 patients in the low risk group 19 (4%) developed a VTE. CONCLUSION: Newly diagnosed cancer patients can be readily stratified into intermediate-high and low risk of VTE using our novel CPMS system. This innovative tool can be used to facilitate customized management decisions regarding VTE prophylaxis for intermediate-high risk patients based their individual risk factors.