Collagen-I influences the post-translational regulation, binding partners and role of Annexin A2 in breast cancer progression.

Introduction: The extracellular matrix (ECM) has been heavily implicated in the development and progression of cancer. We have previously shown that Annexin A2 is integral in the migration and invasion of breast cancer cells and in the clinical progression of ER-negative breast cancer, processes which are highly influenced by the surrounding tumor microenvironment and ECM. Methods: We investigated how modulations of the ECM may affect the role of Annexin A2 in MDA-MB-231 breast cancer cells using western blotting, immunofluorescent confocal microscopy and immuno-precipitation mass spectrometry techniques. Results: We have shown that the presence of collagen-I, the main constituent of the ECM, increases the post-translational phosphorylation of Annexin A2 and subsequently causes the translocation of Annexin A2 to the extracellular surface. In the presence of collagen-I, we identified fibronectin as a novel interactor of Annexin A2, using mass spectrometry analysis. We then demonstrated that reducing Annexin A2 expression decreases the degradation of fibronectin by cancer cells and this effect on fibronectin turnover is increased according to collagen-I abundance. Discussion: Our results suggest that Annexin A2's role in promoting cancer progression is mediated by collagen-I and Annexin A2 maybe a therapeutic target in the bi-directional cross-talk between cancer cells and ECM remodeling that supports metastatic cancer progression.

Circulating microRNAs can predict chemotherapy-induced toxicities in patients being treated for primary breast cancer.

PURPOSE: Prescribing NAC for breast cancer is a pragmatic treatment strategy for several reasons; however, certain patients suffer chemotherapy-induced toxicities. Unfortunately, identifying patients at risk of toxicity often proves challenging. MiRNAs are small non-coding RNA molecules which modulate genetic expression. The aim of this study was to determine whether circulating miRNAs are sensitive biomarkers that can identify the patients likely to suffer treatment-related toxicities to neoadjuvant chemotherapy (NAC) for primary breast cancer. METHODS: This secondary exploratory from the prospective, multicentre translational research trial (CTRIAL ICORG10/11-NCT01722851) recruited 101 patients treated with NAC for breast cancer, from eight treatment sites across Ireland. A predetermined five miRNAs panel was quantified using RQ-PCR from patient bloods at diagnosis. MiRNA expression was correlated with chemotherapy-induced toxicities. Regression analyses was performed using SPSS v26.0. RESULTS: One hundred and one patients with median age of 55 years were recruited (range: 25-76). The mean tumour size was 36 mm and 60.4% had nodal involvement (n = 61) Overall, 33.7% of patients developed peripheral neuropathies (n = 34), 28.7% developed neutropenia (n = 29), and 5.9% developed anaemia (n = 6). Reduced miR-195 predicted patients likely to develop neutropenia (P = 0.048), while increased miR-10b predicted those likely to develop anaemia (P = 0.049). Increased miR-145 predicted those experiencing nausea and vomiting (P = 0.019), while decreased miR-21 predicted the development of mucositis (P = 0.008). CONCLUSION: This is the first study which illustrates the value of measuring circulatory miRNA to predict patient-specific toxicities to NAC. These results support the ideology that circulatory miRNAs are biomarkers with utility in predicting chemotherapy toxicity as well as treatment response.

Role of Adipose Derived Stem Cells in Patients with Diabetic Foot Ulcers: Systematic Review and Meta-Analysis of Randomised Controlled Trials.

Few studies to date have investigated the role of adipose derived stem cells (ADSCs) in patients with diabetic foot ulcers (DFU). We aimed to conduct a systematic search of the literature to explore the available evidence behind ADSCs application in patients with DFU to establish if it has any added benefit regarding healing rate and healing time in this cohort of patients. The PubMed and Embase databases were searched for eligible studies. Only randomised controlled trials which investigated the impact of ADSCs alone on the healing of DFU were considered eligible and were included for the review. Reported healing rates, time to healing and procedure related complications were collected and analysed. The initial search resulted in 160 papers. Following duplicate removal, 131 papers were screened for eligibility. Only four trials met the study criteria and were included for the final review and analysis. 97 out of 189 patients who were included in the four studies received ADSCs for treatment of DFU whereas the remaining 92 patients received standard measures (control). The median participant age was 62, predominantly male (72.5%). Complete healing was achieved in 83.5% (n = 81) of patients in the ADSC group compared to 52% (n = 48) for patients in the control group at 12 months (OR = 4.8, 95%CI = 2.25 to 10.24, P < 0.0001). Mean healing time in the ADSC group ranged from 31 to 85 days whereas mean healing time in the control group ranged from 42 to 85 days (Pooled weighted mean difference = -10.832856, 95%CI = -22.44 to 0.77, P = 0.0673). No significant procedure related complications were reported in either group. The use of ADSCs in patients with DFU appears to demonstrate improved healing rates. The procedure of ADSC harvest and administration appears to be safe based on the initial reports. Large, randomised trials are needed to establish its role in patients with diabetic foot wounds.

Comparing surgical outcomes of approaches to adrenalectomy - a systematic review and network meta-analysis of randomised clinical trials.

BACKGROUND: No randomised clinical trials (RCTs) have simultaneously compared the safety of open (OA), transperitoneal laparoscopic (TLA), posterior retroperitoneal (PRA), and robotic adrenalectomy (RA) for resecting adrenal tumours. AIM: To evaluate outcomes for OA, TLA, PRA, and RA from RCTs. METHODS: A NMA was performed according to PRISMA-NMA guidelines. Analysis was performed using R packages and Shiny. RESULTS: Eight RCTs with 488 patients were included (mean age: 48.9 years). Overall, 44.5% of patients underwent TLA (217/488), 37.3% underwent PRA (182/488), 16.4% underwent RA (80/488), and just 1.8% patients underwent OA (9/488). The mean tumour size was 35 mm in largest diameter with mean sizes of 44.3 mm for RA, 40.9 mm for OA, 35.5 mm for TLA, and 34.4 mm for PRA (P < 0.001). TLA had the lowest blood loss (mean: 50.6 ml), complication rates (12.4%, 14/113), and conversion to open rates (1.3%, 2/157), while PRA had the shortest intra-operative duration (mean: 94 min), length of hospital stay (mean: 3.7 days), lowest visual analogue scale pain scores post-operatively (mean: 3.7), and was most cost-effective (mean: 1728 euros per case). At NMA, there was a significant increase in blood loss for OA (mean difference (MD): 117.00 ml (95% confidence interval (CI): 1.41-230.00)) with similar blood loss observed for PRA (MD: - 10.50 (95% CI: - 83.40-65.90)) compared to TLA. CONCLUSION: LTA and PRA are important contemporary options in achieving favourable outcomes following adrenalectomy. The next generation of RCTs may be more insightful for comparison surgical outcomes following RA, as this approach is likely to play a future role in minimally invasive adrenalectomy. PROSPERO REGISTRATION: CRD42022301005.

Evaluating the Necessity for Routine Sentinel Lymph Node Biopsy in Postmenopausal Patients Being Treated for Clinically Node Negative Breast Cancer the Era of RxPONDER.

INTRODUCTION: Traditionally, sentinel lymph node biopsy (SLNB) was performed to inform adjuvant chemotherapy prescription and prognosis in breast cancer. Following RxPONDER, the OncotypeDX Recurrence Score (RS) guides adjuvant chemotherapy prescription for all postmenopausal patients with estrogen receptor positive, human epidermal growth factor receptor-2 negative (ER+/HER2-) breast cancer with 0 to 3 positive lymph nodes (0-3 + LN). AIMS: To establish the oncological safety of omitting SLNB in postmenopausal patients with ER+/HER2- breast cancer indicated to undergo SLNB and to evaluate the primary determinants of chemotherapy prescription for these patients. PATIENTS AND METHODS: A retrospective cohort study was undertaken. Cox regression and Kaplan-Meier analyses were performed. Data analytics was performed using SPSS v26.0. RESULTS: Five hundred and seventy five consecutive patients were included (mean age: 66.5 years, range: 45-96). The median follow-up was 97.2 months (range: 3.0-181.6). Of the 575 patients, just 12 patients had positive SLNB (SLNB+) (2.1%). Using Kaplan-Meier analyses, SLNB+ failed to impact recurrence (P = .766) or mortality (P = .310). However, using Cox regression analyses, SLNB+ independently predicted poorer disease-free survival (hazard ratio: 1.001, 95% confidence interval (95% CI): 1.000-1.001, P = .029). Logistic regression analysis identified RS as the sole predictor of chemotherapy prescription (odds ratio: 1.171, 95% CI: 1.097-1.250, P < .001). CONCLUSION: Omitting SLNB may be safe and justifiable in postmenopausal patients with ER+/HER2- breast cancer with clinically negative axillae. Following RxPONDER, RS is the most important guide of chemotherapy use in these patients and SLNB may be less important than previously perceived. Prospective, randomized clinical trials are required to fully establish the oncological safety of omitting SLNB in this setting.

Optimal primary wound closure methods after thyroid and parathyroid surgery: network meta-analysis of randomized clinical trials.

BACKGROUND: At present, there is no consensus on optimal neck wound closure methods after thyroid and parathyroid surgery. The aim of this study was to perform a systematic review and network meta-analysis of RCTs evaluating the optimal neck closure method after thyroid and parathyroid surgery. METHODS: A frequentist random-effects network meta-analysis was performed for RCTs comparing at least two closure methods according to PRISMA-network meta-analysis guidelines. Analysis was performed using R packages and Shiny. RESULTS: Eighteen RCTs evaluating six closure methods (that is adhesive (28.5 per cent, 404 patients), absorbable subcuticular suture (18.1 per cent, 257 patients), non-absorbable subcuticular suture (16.8 per cent, 238 patients), staples (26.3 per cent, 372 patients), steristrips (8.1 per cent, 115 patients), and conventional suture (2.1 per cent, 30 patients)) in 1416 patients were included. At network meta-analysis, there was no difference in complication, infection, dehiscence, or haematoma rates irrespective of closure method used. Staples reduced closure duration versus absorbable subcuticular suture (mean difference (MD) 8.50, 95 per cent c.i. 6.90 to 10.10) and non-absorbable subcuticular suture (MD 0.30, 95 per cent c.i. 0.23 to 0.37), whereas adhesives (MD -1.05, 95 per cent c.i. -1.31 to -0.79) reduced closure time relative to staples. Cosmesis was improved after non-absorbable subcuticular suture (odds ratio (OR) 3.41, 95 per cent c.i. 1.66 to 7.00) relative to staples. Staples reduced patient satisfaction (OR 0.04, 95 per cent c.i. 0.00 to 0.33) and ability to shower (OR 0.04, 95 per cent c.i. 0.00 to 0.33) relative to adhesives. CONCLUSION: Despite staples decreasing closure times, this advantage is offset by reduced patient satisfaction, ability to shower, and cosmesis compared with patients with wounds closed using adhesives, absorbable subcuticular suture, and non-absorbable subcuticular suture. Therefore, these closure methods are favourable for closing neck wounds due to more acceptable patient-reported outcomes, without compromising the safety of the procedure.

Immediate Breast Cancer Reconstruction with or without Dermal Matrix or Synthetic Mesh Support: A Review and Network Meta-Analysis.

BACKGROUND: The use of acellular dermal matrices (ADMs) and synthetic mesh as part of implant-based breast reconstruction (IBBR) has been widely adopted. The authors investigated the clinical efficacy and safety of human ADM (HADM), xenograft ADM (XADM), and synthetic mesh as part of IBBR in postmastectomy patients as compared with previous standard implant reconstruction techniques using only a submuscular pocket for coverage. METHODS: A systematic search for randomized controlled trials and observational studies was performed. A frequentist network meta-analysis was conducted using the R packages netmeta and Shiny. RESULTS: Thirty-one of 2375 studies identified met the predefined inclusion criteria. Traditional submuscular placement (no ADM or mesh) had fewer overall complications compared with HADM [OR, 0.51; credible interval (CrI), 0.34 to 0.74], but there was no significant difference between no ADM or mesh and XADM (OR, 0.63; CrI, 0.29 to 1.32) or synthetic mesh (OR, 0.77; CrI, 0.44 to 1.30). No one treatment was superior with regards to implant loss. No ADM or mesh was associated with fewer infectious complications than HADM (OR, 0.6; CrI, 0.39 to 0.89). Both no ADM or mesh (OR, 0.45; CrI, 0.27 to 0.75) and XADM (OR, 0.46; CrI, 0.23 to 0.88) had reduced seroma compared with HADM. CONCLUSIONS: Selecting the appropriate IBBR should evaluate effectiveness, adverse events, and cost. Although it is difficult to select a universal ideal IBBR, evaluation using this network analysis may help guide both physicians and patients in their choice of procedure, especially in the case of HADM, which in this study was shown to be significantly predisposed to complications of infection and seroma. Randomized data are required comparing XADM versus synthetic meshes, given the similar risk profiles but significant cost discrepancy between the techniques.

Evaluating the Role of Circulating MicroRNAs in Predicting Long-Term Survival Outcomes in Breast Cancer: A Prospective, Multicenter Clinical Trial.

BACKGROUND: While long-term outcomes have improved for patients with breast cancer, 20% to 30% will still develop recurrence, and identifying these patients remains a challenge. MicroRNAs (miRNAs) are small, noncoding molecules that modulate genetic expression and affect oncogenesis. STUDY DESIGN: This prospective, multicenter trial (ICORG10/11-NCT01722851) recruited patients undergoing neoadjuvant chemotherapy across 8 Irish centers. Predetermined miRNAs were quantified from patient whole blood using quantitative reverse transcriptase polymerase chain reaction. Venous sampling was performed at diagnosis (timepoint 1) and midway during neoadjuvant chemotherapy (timepoint 2 [T2]). miRNA expression profiles were correlated with recurrence-free survival (RFS), disease-free survival (DFS), and overall survival. Data analysis was performed using R v3.2.3. RESULTS: A total of 124 patients were recruited with a median age of 55.0 years. The median follow-up was 103.1 months. Increased miR-145 expression at T2 was associated with improved RFS (hazard ratio 0.00; 95% confidence interval [CI] 0.00 to 0.99; p = 0.050). Using survival regression tree analysis, a relative cutoff of increased miR-145 expression greater than 0.222 was associated with improved RFS (p = 0.041). Increased miR-145 expression at T2 trended towards significance in predicting improved DFS (hazard ratio 0.00; 95% CI 0.00 to 1.42; p = 0.067). Using survival regression tree analysis, a relative cutoff of increased miR-145 expression greater than 0.222 was associated with improved DFS (p = 0.012). No miRNAs correlated with overall survival. CONCLUSIONS: ICORG10/11 is the first Irish multicenter, translational research trial evaluating circulatory miRNAs as biomarkers predictive of long-term survival and correlated increased miR-145 expression with enhanced outcomes in early-stage breast cancer. Validation of these findings is required in the next generation of translational research trials.

The role of tranexamic acid in reducing post-operative bleeding and seroma formation in breast surgery: A meta-analysis.

INTRODUCTION: Tranexamic acid (TXA) reduces blood loss and blood transfusion requirements in surgery. Seroma and haematoma formation occur as complications of breast surgery. We aimed to perform a meta-analysis evaluating TXA in reducing post-operative haematoma and seroma formation for breast surgery. METHODS: A systematic review was performed in accordance with PRISMA guidelines. Results were expressed as dichotomous variables pooled as odds ratios (OR) with corresponding 95% confidence intervals (CIs) using the Mantel-Haenszel method. RESULTS: Seven studies including 1446 patients were included. There were 1830 breast surgery procedures performed with TXA administered in 797 cases (43.6%). There was a significant reduction in haematoma rates in the TXA group (TXA: 3.184% (22/691) vs Control: 6.787% (64/943), OR: 0.41, 95% CI: 0.20-0.86, P = 0.020). Based on surgical procedure, haematoma rates were similar for TXA and control groups in cancer surgery (P = 0.230). Haematoma rates reduced following TXA use in cosmetic procedures (TXA: 3.807% (15/394) vs. Control: 9.091% (34/374), OR: 0.41, 95% CI: 0.22-0.75, P = 0.004). Haematoma rates were also reduced in procedures where axillary lymph node dissection (ALND) was not performed; in the TXA group, 3.379% (22/651) developed a haematoma versus 6.623% (60/906) in the control group (OR: 0.45, 95% CI 0.27-0.77, P = 0.003). TXA administration did not impact seroma formation or infection rates. CONCLUSION: Perioperative administration of TXA may impact the incidence of haematoma in breast surgery, particularly in cosmetic procedures and procedures without ALND. Well-designed randomised studies are required to determine its true efficacy. TXA has no effect on seroma formation or infection in breast surgery.

Oncological safety of active surveillance for low-risk ductal carcinoma in situ - a systematic review and meta-analysis.

INTRODUCTION: Current standard of care for patients diagnosed with "low-risk" ductal carcinoma in situ (DCIS) involves surgical resection. Ongoing phase III clinical trials are hoping to establish the oncological safety of active surveillance (AS) in managing "low-risk" DCIS. AIMS: To evaluate the oncological safety of AS versus surgery for "low-risk" DCIS. METHODS: A systematic review was performed in accordance with PRISMA guidelines. Survival outcomes were expressed as dichotomous variables and reported as odds ratios (OR) with 95% confidence intervals (95% CI) using the Mantel-Haenszel method. RESULTS: Four studies including 9626 patients were included, 3.9% of which were managed using AS (374/9626) and 96.1% with surgery (9252/9626). The mean age of included patients was 50.3 years (range: 30-99 years) and mean follow-up was 6.1 years. Invasive cancer detection after surgery and AS were similar (OR: 0.93, 95% CI: 0.41-2.11, P = 0.860, heterogeneity (I2) = 0%). At 5 years, BCSS (surgery 99.5% vs. AS 98.7%, P = 0.116) and OS (surgery 95.8% vs. AS 95.7%, P = 0.876) were similar for both groups. At 10 years, BCSS (surgery 98.7% vs. AS 98.6%, P = 0.789) and OS (surgery 87.9% vs. AS 90.9%, P = 0.183) were similar for both groups. Overall, 10-year OS outcomes were similar for both management strategies (OR: 0.32, 95% CI: 0.02-6.42, P = 0.460, I2 = 69%). CONCLUSION: This study outlines the provisional oncological safety of AS for cases of "low-risk" DCIS. While survival outcomes were comparable for both management strategies, ratification of these results in the ongoing phase III clinical trials is still required prior to changes to current management strategies. PROSPERO REGISTRATION: CRD42022313241.

The impact of liver resection on survival for patients with metastatic breast cancer - A systematic review and meta-analysis.

INTRODUCTION: There is uncertainty surrounding the role of resection as an option for curative treatment of breast cancer with liver metastases (BCLM). AIM: To perform a systematic review and meta-analysis evaluating the role of liver resection for BCLM. METHODS: A systematic review was performed as per PRISMA guidelines. Hazard ratio (HR) for overall survival (OS) and standard error was obtained from each study and expressed using the generic inverse variance method, with a corresponding 95% confidence interval (CI). OS outcomes at 1- 3- and 5-years were expressed as dichotomous variables and pooled as odds ratios (OR) using the Mantel-Haenszel method. RESULTS: Nine studies with 1732 patients were included. Of these, 24.5% underwent surgical resection of BCLM (424/1732) and 75.5% did not (1308/1732). Overall, OS was significantly better among those who underwent surgery versus controls (HR: 0.69, 95% CI: 0.59-0.80, P < 0.00001). Mortality rates were significantly reduced at 1-year (7.5% (10/134) vs 20.3% (79/390), OR: 0.25, 95% CI: 0.08-0.74, P = 0.010) and 5-years (54.0% (190/352) vs 75.3% (940/1249), OR: 0.46, 95% CI: 0.25-0.87, P = 0.020) respectively for those undergoing surgery versus controls. Mortality rates at 3 years after surgery were lower than the control group (19.1% (29/152) vs 53.0% (222/419)), however this failed to achieve statistical significance at meta-analysis (OR: 0.32, 95% CI: 0.09-1.12, P = 0.070). CONCLUSION: Liver resection may be considered at multidisciplinary meetings for those with BCLM and offers a potentially curative option. However, judicious patient selection is crucial prior to making decisions in relation to resection of BCLM.

A radiomic model to classify response to neoadjuvant chemotherapy in breast cancer.

BACKGROUND: Medical image analysis has evolved to facilitate the development of methods for high-throughput extraction of quantitative features that can potentially contribute to the diagnostic and treatment paradigm of cancer. There is a need for further improvement in the accuracy of predictive markers of response to neo-adjuvant chemotherapy (NAC). The aim of this study was to develop a radiomic classifier to enhance current approaches to predicting the response to NAC breast cancer. METHODS: Data on patients treated for breast cancer with NAC prior to surgery who had a pre-NAC dynamic contrast enhanced breast MRI were included. Response to NAC was assessed using the Miller-Payne system on the excised tumor. Tumor segmentation was carried out manually under the supervision of a consultant breast radiologist. Features were selected using least absolute shrinkage selection operator regression. A support vector machine learning model was used to classify response to NAC. RESULTS: 74 patients were included. Patients were classified as having a poor response to NAC (reduction in cellularity < 90%, n = 44) and an excellent response (> 90% reduction in cellularity, n = 30). 4 radiomics features (discretized kurtosis, NGDLM contrast, GLZLM_SZE and GLZLM_ZP) were identified as pertinent predictors of response to NAC. A SVM model using these features stratified patients into poor and excellent response groups producing an AUC of 0.75. Addition of estrogen receptor status improved the accuracy of the model with an AUC of 0.811. CONCLUSION: This study identified a radiomic classifier incorporating 4 radiomics features to augment subtype based classification of response to NAC in breast cancer.

Comparison of the Nottingham Prognostic Index and OncotypeDX© recurrence score in predicting outcome in estrogen receptor positive breast cancer.

INTRODUCTION: Traditionally, Nottingham prognostic index (NPI) informed prognosis in patients with estrogen receptor positive, human epidermal growth factor receptor-2 negative, node negative (ER+/HER2-/LN-) breast cancer. At present, OncotypeDX© Recurrence Score (RS) predicts prognosis and response to adjuvant chemotherapy (AC). AIMS: To compare NPI and RS for estimating prognosis in ER + breast cancer. METHODS: Consecutive patients with ER+/HER2-/LN- disease were included. Disease-free (DFS) and overall survival (OS) were determined using Kaplan-Meier and Cox regression analyses. RESULTS: 1471 patients met inclusion criteria. The mean follow-up was 110.7months. NPI was calculable for 1382 patients: 19.8% had NPI≤2.4 (291/1471), 33.0% had NPI 2.41-3.4 (486/1471), 30.0% had NPI 3.41-4.4 (441/1471), 10.9% had NPI 4.41-5.4 (160/1471), and 0.3% had NPI>5.4 (4/1471). In total, 329 patients underwent RS (mean RS: 18.7) and 82.1% had RS < 25 (270/329) and 17.9% had RS ≥ 25 (59/329). Using multivariable Cox regression analyses (n = 1382), NPI independently predicted DFS (Hazard ratio (HR): 1.357, 95% confidence interval (CI): 1.140-1.616, P < 0.001) and OS (HR: 1.003, 95% CI: 1.001-1.006, P = 0.024). When performing a focused analysis of those who underwent both NPI and RS (n = 329), neither biomarker predicted DFS or OS. Using Kaplan Meier analyses, NPI category predicted DFS (P = 0.008) and (P = 0.026) OS. Conversely, 21-gene RS group failed to predict DFS (P = 0.187) and OS (P = 0.296). CONCLUSION: In our focused analysis, neither NPI nor RS predicted survival outcomes. However, in the entire series, NPI independently predicted both DFS and OS. On the 40th anniversary since its derivation, NPI continues to provide accurate prognostication in breast cancer, outperforming RS in the current study.

The Impact of Chemotherapy Prescription on Long-Term Survival Outcomes in Early-Stage Invasive Lobular Carcinoma - A Systematic Review and Meta-Analysis.

INTRODUCTION: Invasive lobular carcinoma (ILCs) are typically endocrine responsive breast cancers which respond poorly to chemotherapy. The long-term survival advantage of prescribing chemotherapy in such cases remains unclear. To perform a systematic review and meta-analysis assessing, the impact of prescribing chemotherapy in such patients on long-term disease-free (DFS) and overall (OS) survival outcomes. METHODS: A systematic review and meta-analysis was performed in accordance with the PRISMA guidelines. Ten-year DFS and OS were pooled as odds ratios (ORs) with 95% confidence intervals (CI) using the Mantel-Haenszel method. Time-to-effect modelling was performed using the generic inverse variance method. RESULTS: Overall, 9 studies including 28,218 patients were included. The mean follow-up was 74 months (range: 0-150 months) and mean age was 60 years (range: 22-90 years). Of these, 34.7% received chemotherapy (9,797/28,218) and 66.3% did not receive chemotherapy (18,421/28,218). Chemotherapy prescription failed to improve 10-year DFS (OR: 0.89, 95% CI: 0.65-1.23) and OS (OR: 0.92, 95% CI: 0.72-1.18). When using time-to-effect modelling, chemotherapy prescription failed to improve DFS (hazard ratio (HR): 1.01, 95% CI: 0.78-1.31) and OS (HR: 1.07, 95% CI: 0.89-1.27, I2= 67%). CONCLUSION: This meta-analysis illustrates no long-term survival advantage associated with chemotherapy prescription in the setting of early-stage ILC. In the absence of well-designed, prospective clinical trials evaluating the impact of chemotherapy on long-term outcomes in ILC, these results should be considered by the multidisciplinary team when deciding on the value of systemic chemotherapy prescription in ILC.

Hypocalcaemia following thyroidectomy among patients who have previously undergone bariatric surgery: systematic review and meta-analysis.

BACKGROUND: Hypocalcaemia is a common complication after thyroidectomy. Bariatric surgery is associated with significant changes in calcium metabolism. Some studies have identified bariatric surgery as a risk factor for hypocalcaemia after thyroidectomy. This systematic review and meta-analysis assessed whether a history of bariatric surgery was associated with an increased risk of hypocalcaemia after thyroidectomy. METHODS: This prospectively registered systematic review (PROSPERO; CRD42021295423) was performed in accordance with PRISMA guidelines. Meta-analysis was undertaken using the Mantel-Haenszel method, with outcomes reported as ORs with 95 per cent confidence intervals. RESULTS: Twenty studies were included in the qualitative synthesis. Five studies incorporating 19 547 patients met the inclusion criteria for meta-analysis, of whom 196 (1.0 per cent) had a history of bariatric surgery. Patients with a history of bariatric surgery were more likely to develop hypocalcaemia after thyroidectomy (30.6 versus 13.0 per cent; OR 3.90, 95 per cent c.i. 1.50 to 10.12; P = 0.005). Among those with a history of bariatric surgery, patients who underwent a bypass procedure were more likely to develop hypocalcaemia after thyroidectomy than those who had a restrictive procedure (38 versus 23 per cent; OR 2.12, 1.14 to 3.97; P = 0.020). CONCLUSION: Patients with a history of bariatric surgery have a significantly greater risk of hypocalcaemia after thyroidectomy, with a heightened risk among those who have had a bypass procedure. Surgeons performing thyroid surgery should be aware of the increased risk of hypocalcaemia after thyroidectomy among these patients.

Low calcium levels are a common complication after surgical removal of the thyroid gland. Patients who have had weight loss surgery (bariatric surgery) have altered calcium metabolism and are prone to low calcium levels. This study assessed whether previous weight loss surgery increased the risk of low calcium levels after thyroid surgery. A search was made of previously published studies assessing the relationship between previous weight loss surgery and low calcium levels after thyroid surgery. Studies have shown that previous weight loss surgery makes patients more than three times more likely to have low calcium levels after thyroid surgery. Management of low calcium in these patients is more challenging than in patients who have not had weight loss surgery. Surgeons performing thyroid surgery need to be aware of whether a patient has previously had weight loss surgery as they have an increased risk of low calcium after thyroid surgery.

Intra-operative nerve monitoring and recurrent laryngeal nerve injury during thyroid surgery: a network meta-analysis of prospective studies.

PURPOSE: Recurrent laryngeal nerve (RLN) injury is a feared complication of thyroid surgery occurring in 1-5% of cases. The present approaches to RLN preservation include RLN visualization with no nerve monitoring (No-NM), intermittent intra-operative nerve monitoring (I-IONM) and continuous intra-operative nerve monitoring (C-IONM). There is ambiguity as to which of these strategies should be the preferred method of RLN preservation. METHODS: A systematic review of the PubMed, Embase and the Cochrane Collaboration databases was undertaken with network meta-analysis (NMA) performed according to the PRISMA and Cochrane Collaboration guidelines. A Bayesian NMA was conducted using R packages netmeta with outcomes expressed as odds ratios (ORs) with 95% credible intervals (CrI). Only prospective studies were included. RESULTS: Eighteen studies met inclusion criteria, including 22,080 patients and 40,642 nerves at risk (NAR). Overall, 23,364 NARs (57.5%) underwent I-IONM, 17,176 (42.3%) No-NM and 98 (0.2%) underwent C-IONM. There were no significant differences between groups regarding the incidence of permanent RLN injury following thyroid surgery (I-IONM vs.No-NM, OR 0.84, 95% CrI 0.55-1.19; C-IONM vs. No-NM, OR 0.44, 95% CrI 0.02-5.00). Pooled analysis showed that IONM (I-IONM or C-IONM) demonstrated a protective effect versus No-NM in reducing the incidence of transient RLN injury (OR 0.75, 95% CI 0.59-0.97, p = 0.03). CONCLUSIONS: IONM strategies did not significantly reduce the incidence of permanent RLN injury following thyroid surgery. However, the small number of C-IONM NARs limits conclusions that may be drawn. Further well-designed prospective studies will be required to definitively assess the utility of C-IONM.

A Novel Surrogate Nomogram Capable of Predicting OncotypeDX Recurrence Score©.

Background: OncotypeDX Recurrence Score© (RS) is a commercially available 21-gene expression assay which estimates prognosis and guides chemoendocrine prescription in early-stage estrogen-receptor positive, human epidermal growth factor receptor-2-negative (ER+/HER2−) breast cancer. Limitations of RS testing include the cost and turnaround time of several weeks. Aim: Our aim is to develop a user-friendly surrogate nomogram capable of predicting RS. Methods: Multivariable linear regression analyses were performed to determine predictors of RS and RS > 25. Receiver operating characteristic analysis produced an area under the curve (AUC) for each model, with training and test sets were composed of 70.3% (n = 315) and 29.7% (n = 133). A dynamic, user-friendly nomogram was built to predict RS using R (version 4.0.3). Results: 448 consecutive patients who underwent RS testing were included (median age: 58 years). Using multivariable regression analyses, postmenopausal status (ß-Coefficient: 0.25, 95% confidence intervals (CIs): 0.03−0.48, p = 0.028), grade 3 disease (ß-Coefficient: 0.28, 95% CIs: 0.03−0.52, p = 0.026), and estrogen receptor (ER) score (ß-Coefficient: −0.14, 95% CIs: −0.22−−0.06, p = 0.001) all independently predicted RS, with AUC of 0.719. Using multivariable regression analyses, grade 3 disease (odds ratio (OR): 5.67, 95% CIs: 1.32−40.00, p = 0.037), decreased ER score (OR: 1.33, 95% CIs: 1.02−1.66, p = 0.050) and decreased progesterone receptor score (OR: 1.16, 95% CIs: 1.06−1.25, p = 0.002) all independently predicted RS > 25, with AUC of 0.740 for the static and dynamic online nomogram model. Conclusions: This study designed and validated an online user-friendly nomogram from routinely available clinicopathological parameters capable of predicting outcomes of the 21-gene RS expression assay.

Evaluating the Role of Circulating MicroRNAs to Aid Therapeutic Decision Making for Neoadjuvant Chemotherapy in Breast Cancer: A Prospective, Multicenter Clinical Trial.

OBJECTIVE: To evaluate whether circulating micro ribonucleic acids (miRNAs) predict response to neoadjuvant chemotherapy (NAC) and inform decision-making in breast cancer patients. INTRODUCTION: Deciphering response to NAC remains a challenge. Those unlikely to respond may benefit from NAC de-escalation before completion, while "responders" should complete treatment. Establishing biomarkers which identify response to NAC is imperative to personalize treatment strategies. miRNAs are small noncoding RNA molecules which modulate genetic expression. miRNAs are believed to inform response to NAC. METHODS: This prospective, multicenter trial (NCT01722851) recruited 120 patients treated with NAC across 8 Irish treatment sites. Predetermined miRNAs were quantified from patient whole bloods using relative quantification polymerase chain reactiond. Venous sampling was performed at diagnosis and midway during NAC. Trends in miRNA expression between timepoints were correlated with treatment response. Data analysis was performed using R 3.2.3. RESULTS: A total of 120 patients were included (median age: 55 years). Overall, 49.2% had luminal breast cancers (59/120), 17.5% luminal B (L/HER2) (21/120), 12.5% human epidermal growth factor receptor-2 positive (HER2+) (15/120), and 20.8% triple negative disease (25/120). In total, 46.7% of patients responded to NAC (56/125) and 26.7% achieved a pathological complete response (pCR) (32/120). For patients with L/HER2, increased Let-7a predicted response to NAC ( P =0.049), while decreased miR-145 predicted response to NAC in HER2+ ( P =0.033). For patients with luminal breast cancers, reduced Let-7a predicted achieving a pCR ( P =0.037) and reduced miR-145 predicted achieving a pCR to NAC in HER2+ ( P =0.027). CONCLUSIONS: This study illustrates the potential value of circulatory miRNA measurement in predicting response to NAC. Further interrogation of these findings may see miRNAs personalize therapeutic decision-making for patients undergoing NAC for early breast cancer.

Evaluation of human adipose-derived stromal cell behaviour following exposure to Tamoxifen.

BACKGROUND AND AIM: Adipose-derived stromal cells (ASCs) are a promising cell source for novel tissue engineering approaches to breast reconstruction following cancer resection. However there is limited knowledge on the effect of adjuvant therapies such as hormonal therapy on ASCs, which may affect their efficacy in regenerative strategies. The present study aims to investigate the effects of Tamoxifen and its metabolites Afimoxifene (4-Hydroxy-Tamoxifen) and Endoxifen (N-desmethyl-4-hydroxytamoxifen) on patient-derived ASC viability, apoptosis, adipogenic differentiation and angiogenic potential. METHODS: ASCs were isolated from fat harvested from female breast cancer patients undergoing breast reconstruction surgery or cosmetic procedures. Oestrogen receptor (ER α, ß) expression was analysed using immunofluorescence. ASCs were then treated with various concentrations of Afimoxifene, Endoxifen and Tamoxifen (combination), and the impact on ASC viability and apoptosis determined. ASCs were cultured in adipogenic-differentiation media with or without tamoxifen and derivatives, and adipogenesis was measured using quantitative Real-time Polymerase chain reaction (qRT-PCR) and histological staining (Oil Red O). The effect on secreted VEGF levels was also quantified in ASC conditioned media RESULTS: ASCs were successfully isolated and characterised from human abdominal lipoaspirates or fat tissues (n = 8). ASCs subjected to varying doses of Tamoxifen and metabolites (up to 1000 nM) showed no decline in cell viability or increase in apoptosis, at physiological doses (upto 100 nM). Functional decline in adipogenic differentiation or gene expression was observed at supraphysiological concentrations of Tamoxifen (1000 nM). VEGF165 protein secretion in ASC-cell conditioned media was not significantly impacted irrespective of dosage. CONCLUSION: At physiologically relevant doses, Tamoxifen treatment did not result in any deleterious effect on ASC survival and functionality and is unlikely to negatively impact ASC based breast reconstruction strategies for breast cancer patients receiving this adjuvant hormonal therapy.

Preoperative Breast Magnetic Resonance Imaging as a Predictor of Response to Neoadjuvant Chemotherapy.

Introduction: The ability to accurately predict pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) in breast cancer would improve patient selection for specific treatment strategies, would provide important information for patients to aid in the treatment selection process, and could potentially avoid the need for more extensive surgery. The diagnostic performance of magnetic resonance imaging (MRI) in predicting pCR has previously been studied, with mixed results. Magnetic resonance imaging performance may also be influenced by tumour and patient factors. Methods: Eighty-seven breast cancer patients who underwent NAC were studied. Pre-NAC and post-NAC MRI findings were compared with pathologic findings postsurgical excision. The impact of patient and tumour characteristics on MRI accuracy was evaluated. Results: The mean (SD) age of participants was 48.7 (10.3) years. The rate of pCR based on post-NAC MRI was 19.5% overall (19/87). The sensitivity, specificity, positive predictive value (PPV), negative predictive value, and accuracy in predicting pCR were 52.9%, 77.1%, 36.0%, 87.1%, and 72.4%, respectively. Positive predictive value was the highest in nonluminal versus Luminal A disease (45.0% vs 25.0%, P < .001), with higher rates of false positivity in nonluminal subtypes (P = .002). Tumour grade, T category, and histological subtype were all independent predictors of MRI accuracy regarding post-NAC tumour size. Conclusion: Magnetic resonance imaging alone is insufficient to accurately predict pCR in breast cancer patients post-NAC. Magnetic resonance imaging predictions of pCR are more accurate in nonluminal subtypes. Tumour grade, T category, and histological subtype should be considered when evaluating post-NAC tumour sizes.