Conceptualizing Scaffold Guided Breast Tissue Regeneration in a Preclinical Large Animal Model.

Scaffold-guided breast tissue regeneration (SGBTR) can transform both reconstructive and cosmetic breast surgery. Implant-based surgery is the most common method. However, there are inherent limitations, as it involves replacement of tissue rather than regeneration. Regenerating autologous soft tissue has the potential to provide a more like-for-like reconstruction with minimal morbidity. Our SGBTR approach regenerates soft tissue by implanting additively manufactured bioresorbable scaffolds filled with autologous fat graft. A pre-clinical large animal study was conducted by implanting 100 mL breast scaffolds (n = 55) made from medical-grade polycaprolactone into 11 minipigs for 12 months. Various treatment groups were investigated where immediate or delayed autologous fat graft, as well as platelet rich plasma, were added to the scaffolds. Computed tomography and magnetic resonance imaging were performed on explanted scaffolds to determine the volume and distribution of the regenerated tissue. Histological analysis was performed to confirm the tissue type. At 12 months, we were able to regenerate and sustain a mean soft tissue volume of 60.9 ± 4.5 mL (95% CI) across all treatment groups. There was no evidence of capsule formation. There were no immediate or long-term post-operative complications. In conclusion, we were able to regenerate clinically relevant soft tissue volumes utilizing SGBTR in a pre-clinical large animal model.

10-Year axillary recurrence in the RACS SNAC1 randomised trial of sentinel lymph node-based management versus routine axillary lymph node dissection.

BACKGROUND: Sentinel node-based management (SNBM) is the international standard of care for early breast cancer that is clinically node-negative based on randomised trials comparing it with axillary lymph node dissection (ALND) and reporting similar rates of axillary recurrence (AR) without distant disease. We report all ARs, overall survival, and breast cancer-specific survival at 10-years in SNAC1. METHODS: 1.088 women with clinically node-negative, unifocal breast cancers 3 cm or less in diameter were randomly assigned to either SNBM with ALND if the sentinel node (SN) was positive, or to SN biopsy followed by ALND regardless of SN involvement. RESULTS: First ARs were more frequent in those assigned SNBM rather than ALND (11 events, cumulative risk at 10-years 1·85%, 95% CI 0·95-3.27% versus 2 events, 0·37%, 95% CI 0·08-1·26%; HR 5·47, 95% CI 1·21-24·63; p = 0·013). Disease-free survival, breast cancer-specific survival, and overall survival were similar in those assigned SNBM versus ALND. Lymphovascular invasion was an independent predictor of AR (HR 6·6, 95% CI 2·25-19·36, p < 0·001). CONCLUSION: First ARs were more frequent with SNBM than ALND in women with small, unifocal breast cancers when all first axillary events were considered. We recommend that studies of axillary treatment should report all ARs to give an accurate indication of treatment effects. The absolute frequency of AR was low in women meeting our eligibility criteria, and SNBM should remain the treatment of choice in this group. However, for those with higher-risk breast cancers, further study is needed because the estimated risk of AR might alter their choice of axillary surgery.

Assessing variability in breast cancer management across the world: results of a questionnaire survey amongst global international experts in breast cancer management.

Background: Breast cancer is the most common cancer in women worldwide with an estimated 2.3 million breast cancer cases diagnosed annually. The outcome of breast cancer management varies widely across the globe which could be due to a multitude of factors. Hence, a blanket approach in standardisation of care across the world is neither practical nor feasible. Aim: To assess the extent and type of variability in breast cancer management across the globe and to do a gap analysis of patient care pathway. Method: An online questionnaire survey and virtual consensus meeting was carried out amongst 31 experts from 25 countries in the field of breast cancer surgical management. The questionnaire was designed to understand the variability in diagnosis and treatment of breast cancer, and potential factors contributing to this heterogeneity. Result: The questionnaire survey shows a wide variation in breast surgical training, diagnosis and treatment pathways for breast cancer patients. There are several factors such as socioeconomic status, patient culture and preferences, lack of national screening programmes and training, and paucity of resources, which are barriers to the consistent delivery of high-quality care in different parts of the world. Conclusion: On-line survey platforms distributed to global experts in breast cancer care can assess gaps in the diagnosis and treatment of breast cancer patients. This survey confirms the need for an in-depth gap analysis of patient care pathways and treatments to enable the development of personalised plans and policies to standardise high quality care.

A Novel Breast-Conserving Surgical Technique in the Management of Phyllodes Tumours of the Breast.

BACKGROUND: Despite advances in oncoplastic breast-conserving techniques, very large phyllodes tumours (PT) may still be recommended for mastectomy. METHODS: We report a novel 2-staged breast-conserving technique that enables smaller excisional volumes whilst maintaining safe oncological excision. Stage-1 is a capsular dissection via a posterior glandular approach without sacrifice of native breast volume. Stage-2 is a delayed localised resection of the seroma cavity providing a circumferential "margin". Two cases are presented. CONCLUSION: This novel technique preserves the breast, optimises cosmesis and is a safe approach to the surgical management of large PT.

Nipple Reconstruction: A Regenerative Medicine Approach Using 3D-Printed Tissue Scaffolds.

IMPACT STATEMENT: This work provides a comprehensive overview and critique of nipple reconstruction techniques to date. It then explores different tissue engineering concepts and how these may improve clinical outcomes for patients undergoing nipple reconstruction. A novel technique is proposed, whereby a three-dimensional-printed tissue-engineered construct is used as an autologous graft to assist nipple reconstruction.

Paradigm shift in the local treatment of breast cancer: mastectomy to breast conservation surgery.

There have been fundamental changes in the approach to breast cancer management over the last century but the primary objective of achieving oncological safety remains unchanged. This evolution is highlighted with a summary of the key evidences in support of the oncological safety of breast conserving surgery (BCS) in early breast cancer (EBC) management. We will also discuss the increasingly pivotal role that neoadjuvant chemotherapy (NACT) may play, in the local treatment of EBC and locally advanced breast cancer (LABC) and the long-term surgical and oncological outcomes.

Breast Augmentation and Reconstruction from a Regenerative Medicine Point of View: State of the Art and Future Perspectives.

Breast reconstruction and augmentation are very common procedures, yet the prevailing current methods utilize silicone implants that may have significant local complications requiring reoperation. Lipofillling is increasingly used to contour and is considered safe, however, its utility is limited by significant volume loss. A new approach could offer an alternative and increase the scope of patient choice. A small number of teams around the world are investigating a breast tissue engineering (TE) paradigm. Conventional breast TE concepts are based on seeding a scaffold with the patients' own stem cells. However, the clinical viability of many of these approaches is limited by their costs in relevant volumes. In this article the state of the art of tissue-engineered breast reconstruction is reviewed and future perspectives are presented and discussed.

Sentinel-Lymph-Node-Based Management or Routine Axillary Clearance? Five-Year Outcomes of the RACS Sentinel Node Biopsy Versus Axillary Clearance (SNAC) 1 Trial: Assessment and Incidence of True Lymphedema.

PURPOSE: To determine whether the benefits of sentinel-node-based management (SNBM) over routine axillary clearance (RAC) persisted to 5 years. METHODS: A total of 1088 women with breast cancer less than 3 cm in diameter and clinically negative axillary nodes were randomized to SNBM with axillary clearance if the sentinel node was positive or RAC preceded by sentinel-node biopsy. The outcomes were: (1) objectively measured change in the volume of the operated and contralateral nonoperated arms; (2) the proportion with an increase in arm volume <15%; and (3) subjectively assessed arm morbidity for the domains swelling, symptoms, dysfunction, and disability. Assessments were performed at 1 and 6 months after surgery and then annually. RESULTS: Limb volume increased progressively in the operated and nonoperated arms for 2 years and persisted unchanged to year 5, accompanied by weight gain. Correction by change in the nonoperated arm showed a mean volume increase of 70 mL in the RAC group and 26 mL in the SNBM group (P < 0.001) at 5 years. Only 28 patients (3.3%) had a corrected increase >15% from baseline (RAC 5.0% vs. SNBM 1.7%). Significant predictors were surgery type (RAC vs. SNBM), obesity, diabetes, palpable tumor, and weight gain exceeding 10% of baseline value. CONCLUSIONS: Subjective assessments revealed persisting patient concerns about swelling and symptoms but not overall disability at 5 years. Subjective scores were only moderately correlated with volume increase. SNAC1 has demonstrated that objective morbidity and subjective morbidity persist for 5 years after surgery and that SNBM significantly lowers the risk of both.

Development and piloting of a decision aid for women considering participation in the Sentinel Node Biopsy versus Axillary Clearance 2 breast cancer trial.

BACKGROUND/AIMS: This study aimed to (1) develop a decision aid for women considering participation in the Sentinel Node Biopsy versus Axillary Clearance 2 (SNAC-2) breast cancer surgical trial and (2) obtain evidence on its acceptability, feasibility, and potential efficacy in routine trial clinical practice via a two-stage pilot. METHODS: The decision aid was developed according to International Patient Decision Aid Standards. Study 1: an initial pilot involved 25 members of the consumer advocacy group, Breast Cancer Network Australia. Study 2: the main pilot involved 20 women eligible to participate in the SNAC-2 trial in New Zealand. In both pilots, a questionnaire assessed: information and involvement preferences, decisional conflict, SNAC-2 trial-related understanding and attitudes, psychological distress, and general decision aid feedback. A follow-up telephone interview elicited more detailed feedback on the decision aid design and content. RESULTS: In both pilots, participants indicated good subjective and objective understanding of SNAC-2 trial and reported low decisional conflict and anxiety. The decision aid was found helpful when deciding about trial participation and provided additional, useful information to the standard trial information sheet. CONCLUSION: The development and two-stage piloting process for this decision aid resulted in a resource that women found very acceptable and helpful in assisting decision-making about SNAC-2 trial participation. The process and findings provide a guide for developing other trial decision aids.

Identification of the sentinel lymph node in the SNAC-1 trial.

BACKGROUND: A combination of scintigraphy and a lymphotropic dye (patent blue dye (BD)) is the recommended technique to detect the sentinel lymph node (SLN) in early breast cancer. This study determined the effect of clinical factors on SLN identification in the sentinel node biopsy versus axillary clearance (SNAC) trial. METHODS: A total of 1088 women were registered. Lymphatic mapping was performed using preoperative lymphoscintigraphy (LSG) and gamma probe (GP) combined with peritumoural injection of patent BD (971 patients) or BD alone (106 patients). RESULTS: SLNs were identified in 1024 women (94%), localized with LSG in 779 (81.4%), and were identified by GP in 879 (91.8%). The BD identified SLNs in 890 of 1073 (82%) women. Three patients had allergic reactions. BD detected the SLNs in 141 of 178 women with negative LSG mapping and in 44 of 79 women with no hot SLNs detected intraoperatively. Age, body mass index (BMI) and tumour presentation (screen detected versus symptomatic) were significantly related to the identification of the SLN. For BD, the primary tumour location was significantly related to identification rate. The detection of blue SLN was significantly lower in women with inner quadrant tumours. CONCLUSION: The combined technique resulted in a high identification rate. BD contributed to the identification of the SLNs in patients where LSG and GP failed to identify the sentinel node. Special attention to these techniques is needed in particular groups of patients such as those with high BMI, screen-detected primary tumours and tumour located in the inner quadrants.

Sentinel lymph node based management or routine axillary clearance? Three-year outcomes of the RACS sentinel node biopsy versus axillary clearance (SNAC) 1 trial.

PURPOSE: To determine whether the benefits of sentinel node based management (SNBM) over routine axillary clearance (RAC) at 1 year persisted to 3 years of follow-up. METHODS: A total of 1,088 women with clinically node-negative breast cancer were randomly assigned to the SNBM or RAC group. Upper limb volume, symptoms, and function were assessed at 1, 6, 12, 24, and 36 months after surgery objectively with upper limb measurements by clinicians and subjectively by patients' using validated self-rating scales. RESULTS: Upper limb volume increased in both groups over the first 2 years and differed between the two groups all time points beyond 1 month (P < 0.02) but then plateaued. Upper limb swelling was no worse in women who had axillary clearance as a two-stage procedure than in women assigned RAC as a one-stage procedure. Upper limb volume had increased 15 % or more in 6.0 % at 6 months and 17.6 % at 3 years in those assigned RAC versus 4.2 and 11.9 % in those assigned SNBM. Reductions in upper limb movement were also greater, with RAC than SNBM over 6 months, but improved and were similar in the two groups from 1 to 3 years. Subjective ratings of upper limb swelling, symptoms, dysfunction, and disability over 3 years were worse in the RAC group. Upper limb swelling at 3 years was rated severe by few women (1.1 %) but was rated as moderate by 9.4 % in the RAC group and 2.5 % in the SNBM group (P < 0.001). CONCLUSIONS: The benefits of SNBM over RAC persist 3 years after surgery.

Is the one-step nucleic acid amplification assay better for intra-operative assessment of breast sentinel nodes?

BACKGROUND: Intra-operative assessment of sentinel lymph nodes in breast cancer offers the opportunity to prevent two-stage surgical procedures. At our institution we employ touch imprint cytology (TIC), which lacks sensitivity. In this study we compare the one-step nucleic acid amplification (OSNA) assay to TIC. METHODS: Imprints were taken from 63 lymph nodes from 35 patients. The lymph nodes were sectioned at 2-mm intervals and alternate slices submitted for either histology or OSNA assay, with histology as the reference standard. RESULTS: Seven patients were histologically positive. Nine and five patients were positive by OSNA and TIC, respectively. Sensitivity, specificity, positive and negative predictive value for the OSNA assay were 85.7%, 85.7%, 63.6% and 96.6% and for TIC were 70.0%, 96.6%, 87.5% and 90.3%. CONCLUSION: In this study OSNA had a higher sensitivity than TIC. Fewer patients assessed by the OSNA assay would have required a two-stage procedure. The OSNA assay appears to be a highly cost-effective method for providing rapid and reliable intra-operative assessment of sentinel lymph nodes.

Sentinel node biopsy and large (≥3 cm) breast cancer.

BACKGROUND: Sentinel node biopsy is an accurate method for staging the axilla in early (small) breast cancers. However, data for the role of this technique for large breast cancers remain limited. METHOD: From the Royal Adelaide Hospital Sentinel Node database and the SNAC trial database, 100 subjects were identified with clinically node negative, large (≥3 cm) primary breast cancer who had undergone sentinel node biopsy and immediate axillary clearance. The pathology results from the sentinel node and axillary specimens were analysed. RESULTS: Average tumour size was 3.91 cm (range 3-10 cm) and 65 of 100 cases had metastatic disease in the axillary nodes. A sentinel node was successfully identified in 93 out of 100 cases with an average of 1.75 sentinel nodes sampled. Sixty-two per cent (58 out of 93) were sentinel node positive and 43% (43 out of 100) had a positive non-sentinel node. The false negative rate following successful sentinel node identification was 4.9% (3 out of 61). CONCLUSION: Sentinel node biopsy was an accurate tool for staging the axilla with a false negative rate comparable to that seen in small tumours. However, given the increased incidence of metastases with larger cancers, further prospective investigation is warranted.

Factors affecting the preoperative and postoperative extracellular fluid in the arm on the side of breast cancer: a cohort study.

BACKGROUND: To explore what factors affect volume of extracellular fluid (ECF) in the arm on the side of surgery pre- and postoperatively and to determine the value of knowing preoperative ECF volume for diagnosis of lymphedema postoperatively. METHODS AND RESULTS: Women (N=516) with early breast cancer were assessed preoperatively and within 4 weeks postoperatively. Baseline measures included inter-arm ECF ratio, side of cancer, number of nodes involved, and other individual characteristics. Postoperative assessment included inter-limb ECF ratio and details from surgery. The postoperative ECF ratio was categorized as to whether it exceeded previously established thresholds, and the change in ECF was categorized as to whether it exceeded 0.1. Linear regression identified which factors explained the variance for preoperative ECF ratio and the change in ratio. Chi square analysis compared whether women categorized using thresholds were the same as those whose ratio increased >0.1 postoperatively. Postoperative ECF ratio was significantly higher than the preoperative ratio (p<0.001). Women whose ECF ratio exceeded previously established thresholds were not the same as those whose ratio increased >0.1 postoperatively (p<0.001). Only the side of surgery explained the preoperative ECF measure; extent of surgery and actual weight explained the change in ECF ratio. CONCLUSION: The ECF ratio preoperatively is not affected by nodal involvement. The change in ECF ratio is affected by the extent of surgery and body mass. Change from preoperative ECF ratio did identify more women at risk for lymphedema than reliance postoperatively on thresholds, supporting preoperative measures.

Intraoperative imprint cytology for breast cancer sentinel nodes: is it worth it?

BACKGROUND: Re-operative surgery is stressful for patients and is an additional burden to an already stretched public health system. Intraoperative confirmation of breast cancer metastases in sentinel lymph nodes (SLNs) provides the necessary information for the surgeon to proceed with immediate axillary dissection, avoiding the need for a second operation, its associated cost, morbidity and adjuvant treatment delays. Our challenge was to implement a technique that was rapid, inexpensive and had a negligible false positive rate. The aim of this study was to determine whether touch imprint cytology (TIC) could reduce returns to theatre without compromising patient safety and pathology department and operating theatre efficiency. METHODS: Intraoperative TIC was performed on bisected SLNs from 134 patients. Post-operatively, specimens were examined as haematoxylin and eosin-stained, paraffin-embedded 2-mm sections. Further sectioning and immunohistochemisty was performed on negative SLNs. RESULTS: The sensitivity of TIC for metastases was 23.8%, the specificity was 100% and the accuracy was 76.1%. Ten patients with macrometastases and none with micrometastastes were detected intraoperatively. The sensitivity of TIC for detecting macrometastases was 34.5%, the accuracy was 78.4% and the specificity was 100%. CONCLUSION: Ten patients avoided a subsequent surgery. The technique caused no theatre delays and the minimal cost was compensated for by the avoidance of a second procedure for a third of patients who definitively required axillary clearance. No patients had an unnecessary axillary clearance and no patients with micrometastases or isolated tumour cells were subjected to an immediate axillary clearance. It would be justifiable to continue this simple, low-cost and non-disruptive approach.

Postsurgical pathology reporting of thyroid cancer in New South Wales, Australia.

BACKGROUND: Clear, accurate, and complete reporting of postsurgical pathology is crucial for the correct evaluation and management of thyroid cancer patients. This study aimed to describe the completeness, as defined by international guidelines, of pathology reporting in a cohort of newly diagnosed thyroid cancer patients in New South Wales (NSW) and to identify factors associated with the completeness of reports. METHODS: Postsurgical pathology reports, held by the NSW Central Cancer Registry, for 448 thyroid cancer patients were reviewed. Presence or absence of recommended key features (tumor histology type, maximum dimension, focality, completeness of excision, extrathyroidal extension, lymphovascular invasion, and lymph node involvement) was recorded. Associations between the number of key items reported and several patient characteristics were investigated. RESULTS: For 285 (63.6%) patients one or more key pathological features were missing, with 177 (39.5%) missing one only, 88 (19.6%) missing two, and 20 (4.5%) missing three or more. Extrathyroidal extension was the most poorly reported key feature, being present in only 228 (50.9%) reports [95% confidence interval 46.2, 55.6]. Pathology reports were less complete for patients with small tumor size (p<0.001) or localized spread (p<0.001). Synoptic reports were significantly more complete than narrative-style reports (98.3% vs. 27.1%, p<0.001). CONCLUSIONS: Postsurgical pathology reporting of differentiated thyroid cancer in NSW was found to be far from complete, with 64% of reports missing information on at least one feature that is considered internationally to be a critical factor in the prognosis and treatment of thyroid cancer patients. Synoptic reporting reduces the number of key features missing from pathology reports.

Tubular breast carcinoma: an argument against treatment de-escalation.

PURPOSE: To evaluate the role of adjuvant radiotherapy in management of patients with tubular carcinoma of the breast. METHODS: One hundred seventy-eight patients treated for tubular carcinoma were identified from the Queensland Radium Institute database. A retrospective review of medical records identified 115 patients meeting eligibility criteria: breast-conserving surgery for a histological diagnosis of tubular carcinoma, minimum follow up of 12 months and adequate medical records. RESULTS: Median follow up was 64 months. There were no significant differences between patient characteristics treated with and without radiotherapy. Median age at diagnosis was 54 (36-78) years. Ninety-five percent tumours were T1 and four patients had positive axillary lymph nodes. Of 94 patients treated with adjuvant radiotherapy, one developed local relapse. Five of 21 patients who did not have adjuvant radiotherapy failed locally. Five-year relapse-free survival with and without radiotherapy was 100 and 89%, respectively (hazard ratio for radiotherapy: 0.06; 95% confidence interval 0.01-0.32, P = 0.001). CONCLUSION: Radiotherapy has a significant impact on relapse-free survival in patients treated with breast-conserving surgery for tubular carcinoma.

Pathways to the diagnosis of thyroid cancer in New South Wales: a population-based cross-sectional study.

BACKGROUND: Over the past few decades, an increase in the incidence of thyroid cancer has been recorded in many countries around the world including Australia. Heightened medical surveillance and increased technological sensitivity could be contributing to greater detection of asymptomatic disease. OBJECTIVES: To describe the pathways to diagnosis of thyroid cancer for a cohort of newly diagnosed patients in New South Wales (NSW), Australia, and compare these pathways by age, sex, place of residence, ethnic background, medical insurance status, and disease characteristics. METHODS: A total of 452 newly diagnosed cases of thyroid cancer were recruited through the population-based NSW Central Cancer Registry. Participants completed a questionnaire and diary of doctor visits and investigations that led to their diagnosis. Tumor characteristics were obtained from pathology reports. RESULTS: Forty percent of patients initially presented to their doctor with a lump or symptom specific to thyroid cancer and 60% had their cancer detected incidentally during a medical encounter. Men were more likely than women to be diagnosed after imaging for another health concern versus reporting a thyroid lump or symptom (p = 0.001). Thyroid cancer diagnosis after imaging for another health concern increased with age (p = 0.023), and larger tumors were less likely to be diagnosed after treatment for a benign thyroid disease (p = 0.040). CONCLUSION: As the majority of participants had incidental diagnoses, the reported incidence of thyroid cancer is likely to be influenced by diagnostic technology and medical surveillance practices. This, however, probably only partly explains the observed rise in the incidence of thyroid cancer in NSW.