Clinicopathological Predictors of Positive Resection Margins in Breast-Conserving Surgery.

BACKGROUND: Ductal carcinoma in situ (DCIS) is associated with risk of positive resection margins following breast-conserving surgery (BCS) and subsequent reoperation. Prior reports grossly underestimate the risk of margin positivity with IBC containing a DCIS component (IBC + DCIS) due to patient-level rather than margin-level analysis. OBJECTIVE: The aim of this study was to delineate the relative risk of IBC + DCIS compared with pure IBC (without a DCIS component) on margin positivity through detailed margin-level interrogation. METHODS: A single institution, retrospective, observational cohort study was conducted in which pathology databases were evaluated to identify patients who underwent BCS over 5 years (2014-2019). Margin-level interrogation included granular detail into the extent, pathological subtype and grade of disease at each resection margin. Predictors of a positive margin were computed using multivariate regression analysis. RESULTS: Clinicopathological details were examined from 5454 margins from 909 women. The relative risk of a positive margin with IBC + DCIS versus pure IBC was 8.76 (95% confidence interval [CI] 6.64-11.56) applying UK Association of Breast Surgery guidelines, and 8.44 (95% CI 6.57-10.84) applying the Society of Surgical Oncology/American Society for Radiation Oncology guidelines. Independent predictors of margin positivity included younger patient age (0.033, 95% CI 0.006-0.060), lower specimen weight (0.045, 95% CI 0.020-0.069), multifocality (0.256, 95% CI 0.137-0.376), lymphovascular invasion (0.138, 95% CI 0.068-0.208) and comedonecrosis (0.113, 95% CI 0.040-0.185). CONCLUSIONS: Compared with pure IBC, the relative risk of a positive margin with IBC + DCIS is approximately ninefold, significantly higher than prior estimates. This margin-level methodology is believed to represent the impact of DCIS more accurately on margin positivity in IBC.

Single-stage buried autologous breast reconstruction (BABR).

BACKGROUND: Breast reconstructive standards are increasingly high oncologically, aesthetically, and practically. Autologous breast reconstruction remains the gold standard which, buried, after nipple-sparing mastectomy (where oncologically safe) or wise pattern reduction for large or ptotic patients, with contralateral symmetrisation where required, enables single-stage reconstruction. However, previous series report prohibitively high revision rates. This series prospectively compares a series of buried and non-buried free flaps for breast reconstruction. METHODS: All breast reconstructions with free autologous tissue transfer, buried or with a cutaneous paddle, conducted over 8 years by a single surgeon were included. Demographic, oncologic and reconstructive details, immediate complications and revision surgeries were recorded and compared between the two groups. RESULTS: A total of 182 free flaps were performed on 156 patients, 69 buried and 113 with cutaneous paddles. There were no significant demographic or complication differences between the two groups. Of the buried group, 51% did not require further surgery compared to 29% of the paddle group. CONCLUSIONS: Buried autologous breast reconstruction is a safe and aesthetic option for breast reconstruction, and potentially single stage. This is particularly true where it is combined with nipple-sparing mastectomy (where oncologically safe) or breast reduction mastectomy, and contralateral symmetrisation, where required. Further research could include patient reported outcome measures and cost analysis.

Patient-level costs of staged unilateral versus immediate bilateral symmetrization mammoplasty in breast-conserving surgery.

BACKGROUND: Following therapeutic mammoplasty (TM), the contralateral breast may require a later balancing procedure to optimize shape and symmetry. The alternative is to offer patients simultaneous TM with immediate contralateral symmetrization via a dual-surgeon approach, with the goal of reducing costs and minimizing the number of subsequent hospital appointments in an era of COVID-19 surges. The aim of this cost-consequence analysis is to characterize the cost-benefit of immediate bilateral symmetrization dual-operator mammoplasty versus staged unilateral single operator for breast cancer surgery. METHOD: A prospective single-centre observational study was conducted at an academic teaching centre for breast cancer surgery in the UK. Pseudonymized data for clinicopathological variables and procedural care information, including the type of initial breast-conserving surgery and subsequent reoperation(s), were extracted from the electronic patient record. Financial data were retrieved using the Patient-Level Information and Costing Systems. RESULTS: Between April 2014 and March 2020, 232 women received either immediate bilateral (n = 44), staged unilateral (n = 57) for breast cancer, or unilateral mammoplasty alone (n = 131). The median (interquartile range (i.q.r.)) additional cost of unilateral mammoplasty with staged versus immediate bilateral mammoplasty was €5500 (€4330 to €6570) per patient (P < 0.001), which represents a total supplementary financial burden of €313 462 to the study institution. There was no significant difference between groups in age, Charlson comorbidity index, operating minutes, time to adjuvant radiotherapy in months, or duration of hospital stay. CONCLUSION: Synchronous dual-surgeon immediate bilateral TM can deliver safe immediate symmetrization and is financially beneficial, without delay to receipt of adjuvant therapy, or additional postoperative morbidity.

Indocyanine green fluorescence image processing techniques for breast cancer macroscopic demarcation.

Re-operation due to disease being inadvertently close to the resection margin is a major challenge in breast conserving surgery (BCS). Indocyanine green (ICG) fluorescence imaging could be used to visualize the tumor boundaries and help surgeons resect disease more efficiently. In this work, ICG fluorescence and color images were acquired with a custom-built camera system from 40 patients treated with BCS. Images were acquired from the tumor in-situ, surgical cavity post-excision, freshly excised tumor and histopathology tumour grossing. Fluorescence image intensity and texture were used as individual or combined predictors in both logistic regression (LR) and support vector machine models to predict the tumor extent. ICG fluorescence spectra in formalin-fixed histopathology grossing tumor were acquired and analyzed. Our results showed that ICG remains in the tissue after formalin fixation. Therefore, tissue imaging could be validated in freshly excised and in formalin-fixed grossing tumor. The trained LR model with combined fluorescence intensity (pixel values) and texture (slope of power spectral density curve) identified the tumor's extent in the grossing images with pixel-level resolution and sensitivity, specificity of 0.75 ± 0.3, 0.89 ± 0.2.This model was applied on tumor in-situ and surgical cavity (post-excision) images to predict tumor presence.

The Impact of Temporal Variation in Indocyanine Green Administration on Tumor Identification During Fluorescence Guided Breast Surgery.

BACKGROUND: On average, 21% of women in the USA treated with Breast Conserving Surgery (BCS) undergo a second operation because of close positive margins. Tumor identification with fluorescence imaging could improve positive margin rates through demarcating location, size, and invasiveness of tumors. We investigated the technique's diagnostic accuracy in detecting tumors during BCS using intravenous indocyanine green (ICG) and a custom-built fluorescence camera system. METHODS: In this single-center prospective clinical study, 40 recruited BCS patients were sub-categorized into two cohorts. In the first 'enhanced permeability and retention' (EPR) cohort, 0.25 mg/kg ICG was injected ~ 25 min prior to tumor excision, and in the second 'angiography' cohort, ~ 5 min prior to tumor excision. Subsequently, an in-house imaging system was used to image the tumor in situ prior to resection, ex vivo following resection, the resection bed, and during grossing in the histopathology laboratory to compare the technique's diagnostic accuracy between the cohorts. RESULTS: The two cohorts were matched in patient and tumor characteristics. The majority of patients had invasive ductal carcinoma with concomitant ductal carcinoma in situ. Tumor-to-background ratio (TBR) in the angiography cohort was superior to the EPR cohort (TBR = 3.18 ± 1.74 vs 2.10 ± 0.92 respectively, p = 0.023). Tumor detection reached sensitivity and specificity scores of 0.82 and 0.93 for the angiography cohort and 0.66 and 0.90 for the EPR cohort, respectively (p = 0.1051 and p = 0.9099). DISCUSSION: ICG administration timing during the angiography phase compared with the EPR phase improved TBR and diagnostic accuracy. Future work will focus on image pattern analysis and adaptation of the camera system to targeting fluorophores specific to breast cancer.

The feasibility and safety of immediate breast reconstruction in the COVID-19 era.

The coronavirus disease-2019 pandemic has had a significant impact on the delivery of surgical services, particularly reconstructive surgery. This article examines the current evidence to assess the feasibility of recommencing immediate breast reconstruction services during the pandemic and highlights considerations required to ensure patient safety.

A measure of case complexity for streamlining workflow in multidisciplinary tumor boards: Mixed methods development and early validation of the MeDiC tool.

BACKGROUND AND OBJECTIVE: There is increasing emphasis in cancer care globally for care to be reviewed and managed by multidisciplinary teams (ie, in tumor boards). Evidence and recommendations suggest that the complexity of each patient case needs to be considered as care is planned; however, no tool currently exists for cancer teams to do so. We report the development and early validation of such a tool. METHODS: We used a mixed-methods approach involving psychometric evaluation and expert review to develop the Measure of case-Discussion Complexity (MeDiC) between May 2014 and November 2016. The study ran in six phases and included ethnographic interviews, observations, surveys, feasibility and reliability testing, expert consensus, and multiple expert-team reviews. RESULTS: Phase-1: case complexity factors identified through literature review and expert interviews; Phase-2: 51 factors subjected to iterative review and content validation by nine cancer teams across four England Trusts with nine further items identified; Phase 3: 60 items subjected to expert review distilled to the most relevant; Phase 4: item weighing and further content validation through a national UK survey; Phases 5 and 6: excellent interassessor reliability between clinical and nonclinical observers, and adequate validity on 903 video case discussions achieved. A final set of 27 factors, measuring clinical and logistical complexities were integrated into MeDiC. CONCLUSIONS: MeDiC is an evidence-based and expert-driven tool that gauges the complexity of cancer cases. MeDiC may be used as a clinical quality assurance and screening tool for tumor board consideration through case selection and prioritization.

Can we see what is invisible? The role of MRI in the evaluation and management of patients with pathological nipple discharge.

INTRODUCTION: The aim of this study was to determine the ability of MRI to identify and assess the extent of disease in patients with pathological nipple discharge (PND) with an occult malignancy not evident on standard pre-operative evaluation with mammography and ultrasound. METHODS: Patients presenting to the breast unit of Imperial College Healthcare NHS Trust between December 2009 and December 2018 with PND and normal imaging were enrolled in the study. Pre-operative bilateral breast MRI was performed in all patients as part of our protocol and all patients were offered diagnostic microdochectomy. RESULTS: A total of 82 patients fulfilled our selection criteria and were enrolled in our study. The presence of an intraductal papilloma (IDP) was identified as the cause of PND in 38 patients (46.3%), 14 patients had duct ectasia (DE-17%) and 5 patients had both an IDP and DE. Other benign causes were identified in 11 patients (13.4%). Despite normal mammography and ultrasound a malignancy was identified in 14 patients (17%). Eleven patients had DCIS (13.4%), two had invasive lobular carcinoma and one patient had an invasive ductal carcinoma. The sensitivity of MRI in detecting an occult malignancy was 85.71% and the specificity was 98.53%. The positive predictive value was 92.31% and the negative predictive value was 97.1%. CONCLUSIONS: Although a negative MRI does not exclude the presence of an occult malignancy the high sensitivity and specificity of this diagnostic modality can guide the surgeon and alter the management of patients with PND.

Training the Trainers of Tomorrow Today - driving excellence in medical education.

Training the Trainers of Tomorrow Today (T4) is a new way to deliver "Training for Trainers". Responding to local dissatisfaction with existing arrangements, T4 builds on 3 essential requirements for a future shape of training: 1. Clinical Leadership and a Collaborative Approach 2. Cross-Specialty Design and Participation 3. Local Delivery and Governance Networks Design principles also included: 3 levels of training to reflect differing needs of clinical supervisors, educational supervisors and medical education leader, mapping to GMC requirements and the London Deanery's Professional Development Framework; alignment of service, educational theory and research; recognition of challenges in delivering and ensuring attendance in busy acute and mental health settings, and the development of a faculty network. The delivery plan took into account census of professional development uptake and GMC Trainee Surveys. Strong engagement and uptake from the 11 Trusts in NW London has been achieved, with powerful penetration into all specialties. Attendance has exceeded expectations. Against an initial 12 month target of 350 attendances, 693 were achieved in the first 8 months. Evaluation of content demonstrates modules are pitched appropriately to attendees needs, with positive feedback from trainers new to the role. Delivery style has attracted high ratings of satisfaction: 87% attendees rating delivery as "good\excellent". External evaluation of impact demonstrated improved training experiences through changes in supervision, the learning environment and understanding of learning styles. We have addressed sustainability of the programme by advertising and recruiting Local Faculty Development Trainers. Volunteer consultants and higher trainees are trained to deliver the programme on a cascade model, supported by the Specialty Tutors, individual coaching and educational bursaries. The Trainers are local champions for excellence in training, provide a communication between the programme and local providers, are a repository of expertise in their service, and trouble shoot local barriers to engagement.

Biological basis of [¹¹C]choline-positron emission tomography in patients with breast cancer: comparison with [¹8F]fluorothymidine positron emission tomography.

OBJECTIVE: The biological significance of [¹¹C]choline (CHO) uptake in human tumours is unclear and probably linked to choline kinase-α (CHKα) expression and cell proliferation. We directly compared CHO with [¹8F]fluorothymidine (FLT), an imaging biomarker of proliferation, by positron emission tomography (PET) in patients with breast cancer to investigate whether cell proliferation is an important determinant of CHO uptake. Furthermore, we evaluated CHKα and the Ki67-labelling index (LIKi67) in tumour biopsies. METHODS: Sequential CHO-PET and FLT-PET within the same imaging session were performed in 21 patients with oestrogen receptor (ER)-positive breast cancer (28 lesions). Average and maximum CHO standardized uptake values (SUV) at 60 min: SUV60,av, and SUV60,max, and the rate constant of net irreversible uptake, Ki, were compared with FLT uptake at 60 min: SUV60,av and SUV60,max. Biopsies were stained for CHKα and LIKi67 in eight cases. RESULTS: Tumours were equally visible on CHO-PET and FLT-PET imaging. Tumour CHO-PET strongly correlated with FLT imaging variables (Pearson's r=0.83; P<0.0001 for CHO-SUV60,max vs. FLT-SUV60,max). A statistically significant association was found between CHO-PET variables and categorical scores of cytoplasmic CHKα intensity and between FLT-PET and LIKi67 (P<0.05, one-way analysis of variance). CONCLUSION: Choline metabolism and proliferation as assessed by PET were correlated in ER-positive breast cancer, indicating that high CHO uptake is a measure of cellular proliferation in this setting. CHO uptake was also found to be related to cytoplasmic CHKα expression.

Management and outcome of HER2-positive early breast cancer treated with or without trastuzumab in the adjuvant trastuzumab era.

BACKGROUND: Adjuvant trastuzumab (AT) is known to significantly improve survival of women with HER2(+) early breast cancer. This study explores the use and nonuse of AT in early breast cancer, as well as the efficacy in a neoadjuvant and adjuvant population, within a routine clinical setting. PATIENTS AND METHODS: Histopathology reports of invasive breast cancer resected at Imperial College Healthcare NHS Trust (ICHT) between January 2006 and December 2008 were reviewed. HER2(+) patients were identified and their case notes reviewed. In addition, patients who received AT at our center but underwent surgery elsewhere were included in the efficacy and safety analyses. RESULTS: The local HER2(+) rate was 13.1%, with 54.5% of these patients receiving AT. A total of 128 patients received AT (85 local and 43 referrals from elsewhere). Neoadjuvant chemotherapy (CT) followed by postoperative AT was associated with a significantly increased risk of recurrence compared with adjuvant CT and then AT (hazard ratio [HR] 18.6 [95% CI, 1.8-152.2]; P = .013). The proportion of patients who were disease free at 3 years from primary therapy was 96.4% (95% CI, 89.8%-100%) for adjuvant therapy, compared with 72.0% (95% CI, 56.5%-91.6%) for neoadjuvant therapy. AT was omitted in 49 HER2(+) patients; the main reason for AT omission was clinical judgment that the breast cancer was low risk. Patients treated with AT had a significantly decreased risk of recurrence (HR 0.27 [95% CI, 0.08-0.97]; P = .04) compared with the untreated patients. The majority of untreated relapses were in patients in whom there was an original intent to use AT. The proportion alive at 3 years for adjuvant CT, neoadjuvant CT, and untreated AT was 100%, 74.5%, and 92.7% respectively. CONCLUSION: The overall efficacy and safety of AT in our routine clinical setting is comparable to the large randomized trials. HER2(+) patients who underwent neoadjuvant CT had a significantly increased risk of disease recurrence compared with patients treated with adjuvant CT followed by trastuzumab. Untreated patients had an increased risk of recurrence.

Schizophrenia does not adversely affect the treatment of women with breast cancer: a cohort study.

BACKGROUND: Data on the natural course of patients with breast cancer and schizophrenia are limited. Although there have been studies in assessing the incidence of breast cancer in the setting of schizophrenia, there is very little information concerning the clinical profile of these women. METHODS: We analyzed the data from our electronic notes system by searching for the terms 'schizophrenia' or 'schizophrenic' and 'breast cancer' or 'tumour' between 1993 and 2009. Information was collected on demographics, clinico-pathologic disease variables, treatment including anti-emetic use, chemotherapy delivery and outcomes. RESULTS: From 90,676 patients screened, we identified 37 individuals who had breast cancer and a pre-existing underlying diagnosis of schizophrenia. Of these, 30 (81%) presented with early breast cancer and 7 (19%) presented with metastatic disease. Node positivity was observed in 14 individuals (38%). The average interval between diagnosis of schizophrenia and breast cancer was more than 20 years in the majority of the patients. Treatment outcomes, trial involvement, compliance and ability to provide informed consent were similar to our previously published cohort data. CONCLUSIONS: Schizophrenia does not affect treatment delivery or outcomes in women with breast cancer. The presence of schizophrenia should not be a limiting factor for entry into clinical trials. Breast cancer patients with this illness should be offered standard treatment without discrimination, including entry into clinical trials.

A rare case of breast carcinoma presenting with paraneoplastic cerebellar degeneration.

This case report highlights the importance of a high index of suspicion for breast cancer in a young patient with rapidly progressive neurological dysfunction, a family history of breast cancer and an asymptomatic breast lump.

The role of SRC-3 in human breast cancer.

Members of the nuclear receptor superfamily are ligand-regulated transcription factors involved in the control of a broad range of normal physiological and disease processes. The estrogen receptor alpha (ERalpha) is a member of the steriod receptor family, which is part of the nuclear receptor superfamily. ERalpha it is important for many biological processes and plays a key role in the pathogenesis of breast cancer. Gene regulation by ERalpha requires the recruitment of a multitude of transcriptional co-regulators to the promoters of estrogen-responsive genes. There is evidence in support of the involvement of these co-regulators in breast cancer progression. We review the role of steroid receptor co-activator-3 (SRC-3), which is frequently amplified in breast cancer, and its role in breast cancer risk, outcome and response to endocrine therapy in patients with breast cancer.

[11C]choline positron emission tomography in estrogen receptor-positive breast cancer.

PURPOSE: Novel radiotracers could potentially allow the identification of clinically aggressive tumor phenotypes. As choline metabolism increases during malignant transformation and progression of human mammary epithelial cells, we examined the ability of [(11)C]choline (CHO) positron emission tomography imaging to detect clinically aggressive phenotype in patients with estrogen receptor (ER)-positive breast cancer in vivo. EXPERIMENTAL DESIGN: CHO positron emission tomography was done in 32 individuals with primary or metastatic ER-positive breast cancer. Semiquantitative (standardized uptake value) and fully quantitative (net irreversible transfer rate constant of CHO, Ki) estimates of CHO uptake in the tumors were calculated and compared with tumor grade, size, involved nodes, and also ER, progesterone receptor, Ki-67, and human epidermal growth factor receptor-2 scores. RESULTS: Breast tumors were well visualized in 30 of 32 patients with good tumor background ratios. A wide range of uptake values were observed in primary and metastatic tumors. CHO uptake variables correlated well with tumor grade. For most imaging variables, a poor association was found with tumor size, ER, progesterone receptor, human epidermal growth factor receptor-2, Ki-67, and nodal status. CONCLUSIONS: CHO showed good uptake in most breast cancers and merits further investigation as a breast cancer imaging agent.