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Introduction: Targeted intraoperative radiotherapy (TARGIT - IORT) as a tumour bed boost after breast conserving surgery is well established for women with early breast cancer. A previous study from our group shows a beneficial effect of TARGIT-IORT on overall survival (OS) but not disease-free survival (DFS) after neoadjuvant chemotherapy compared to an external boost suggesting a potential non-inferiority of TARGIT-IORT. In this study, we present results regarding the high-risk subset of patients (i.e. with triple negative (TN) and HER2 positive tumours) from this cohort. Method: In this non-randomized cohort study involving patients with HER2 positive (n= 28) and triple negative (n=42) tumours after NACT we compared outcomes of 40 patients with tumour bed boost applied with TARGIT IORT during lumpectomy versus 30 patients treated in the previous 13 months with external (EBRT) boost. All patients received whole breast radiotherapy. Rates of DFS and OS were compared. Results: Median follow up was 49 months. In comparison of TARGIT-IORT vs. EBRT 5-year Kaplan- Meier estimates of OS showed no significant difference among patients with HER2 positive tumours (100% vs. 91.7%, log rank p = 0.22). The same was seen for DFS (83.3% vs. 77.0%, log rank p=0.38). The results for TN cases were similar (OS : 87.5% vs. 74.1%, log rank p=0.488; DFS 87.5% vs. 60%, log rank p=0.22). Conclusion: Although survival estimates trended towards favouring TARGIT-IORT, no significant differences could be observed and the significantly positive result for OS favoring TARGIT-IORT in the whole cohort of 116 patients could not be reproduced in this subset analysis of patients with TN and HER2 positive tumours. This may be contributable to the limited number of patients but may also indicate that effects seen in the whole cohort were mainly driven by ER and/or PR positive and HER2 negative tumours. Most importantly, non-inferiority of TARGIT-IORT as an intraoperative boost could be reproduced in these high-risk patients.

OBJECTIVES: A thorough understanding of mitral and aortic valve motion dynamics is essential in mastering the skills necessary for performing successful valve intervention (open or transcatheter repair or replacement). We describe a reproducible and versatile beatingheart mitral and aortic valve assessment and valve intervention training model in human cadavers.METHODS: The model is constructed by bilateral ligation of the pulmonary veins, ligation of the supra-aortic arteries, creating a shunt between the descending thoracic aorta and the left atrial appendage with a vascular prosthesis, anastomizing a vascular prosthesis to the apex and positioning an intra-aortic balloon pump (IABP) in the vascular prosthesis, cross-clamping the descending thoracic aorta, and finally placing a fluid line in the shunt prosthesis. The left ventricle is filled with saline to the desired pressure through the fluid line, and the IABP is switched on and set to a desired frequency (usually 60-80 bpm). Prerepair valve dynamic motion can be studied under direct endoscopic visualization. After assessment, the IABP is switched off, and valve intervention training can be performed using standard techniques.RESULTS: This high-fidelity simulation model has known limitations, but provides a realistic environment with an actual beating (human) heart, which is of incremental value. The model provides a unique opportunity to fill a beating heart with saline and to study prerepair mitral and aortic valve dynamic motion under direct endoscopic visualization.CONCLUSIONS: The entire set-up provides a versatile beating-heart mitral and aortic valve assessment model, which may have important implications for future valve intervention training.

Background: Adjuvant trastuzumab significantly improves outcomes for patients with HER2-positive early breast cancer. The standard treatment duration is 12 months but shorter treatment could provide similar efficacy while reducing toxicities and cost. We aimed to investigate whether 6-month adjuvant trastuzumab treatment is non-inferior to the standard 12-month treatment regarding disease-free survival.Methods: This study is an open-label, randomised phase 3 non-inferiority trial. Patients were recruited from 152 centres in the UK. We randomly assigned patients with HER2-positive early breast cancer, aged 18 years or older, and with a clear indication for chemotherapy, by a computerised minimisation process (1:1), to receive either 6-month or 12-month trastuzumab delivered every 3 weeks intravenously (loading dose of 8 mg/kg followed by maintenance doses of 6 mg/kg) or subcutaneously (600 mg), given in combination with chemotherapy (concurrently or sequentially). The primary endpoint was disease-free survival, analysed by intention to treat, with a non-inferiority margin of 3% for 4-year disease-free survival. Safety was analysed in all patients who received trastuzumab. This trial is registered with EudraCT (number 2006–007018–39), ISRCTN (number 52968807), and ClinicalTrials.gov (number NCT00712140).Findings: Between Oct 4, 2007, and July 31, 2015, 2045 patients were assigned to 12-month trastuzumab treatment and 2044 to 6-month treatment (one patient was excluded because they were double randomised). Median follow-up was 5·4 years (IQR 3·6–6·7) for both treatment groups, during which a disease-free survival event occurred in 265 (13%) of 2043 patients in the 6-month group and 247 (12%) of 2045 patients in the 12-month group. 4-year disease-free survival was 89·4% (95% CI 87·9–90·7) in the 6-month group and 89·8% (88·3–91·1) in the 12-month group (hazard ratio 1·07 [90% CI 0·93–1·24], non-inferiority p=0·011), showing non-inferiority of the 6-month treatment. 6-month trastuzumab treatment resulted in fewer patients reporting severe adverse events (373 [19%] of 1939 patients vs 459 [24%] of 1894 patients, p=0·0002) or stopping early because of cardiotoxicity (61 [3%] of 1939 patients vs 146 [8%] of 1894 patients, pInterpretation: We have shown that 6-month trastuzumab treatment is non-inferior to 12-month treatment in patients with HER2-positive early breast cancer, with less cardiotoxicity and fewer severe adverse events. These results support consideration of reduced duration trastuzumab for women at similar risk of recurrence as to those included in the trial.Funding: UK National Institute for Health Research, Health Technology Assessment Programme.

PurposeTreatment of metastatic colorectal cancer frequently includes anti-angiogenic agents such as bevacizumab. Size measurements are inadequate to assessment treatment response to these agents, and newer response assessment criteria are needed. We aimed to evaluate 18-fluoro-2-deoxyglucose positron emission tomography (18F-FDG PET)-derived texture parameters in a preclinical colorectal cancer model as alternative metrics of response to treatment with bevacizumab. Methods Fourteen CD1 athymic mice injected in the flank with 5 x 106 LS174T cells (human colorectal carcinoma) were either untreated controls (n=7) or bevacizumab treated (n=7). After 2 weeks, mice underwent 18FDG-PET/CT. Calliper-measured tumour growth (Δvol) and final tumour volume (Volcal), 18FDG-PET metabolically active volume (Volmet), mean metabolism (Metmean), and maximum metabolism (Metmax) were measured. Twenty-four texture features were compared between treated and untreated mice. Immunohistochemical mean tumour vascular density (MVD) was estimated by anti-CD-34 staining after tumour resection.ResultsTreated mice had significantly lower MVD (p=0.032), confirming anti-angiogenic therapeutic effect of bevacizumab. None of the conventional measures were different between the two groups: Δvol (p=0.9), Volcal (p=0.7), Volmet (p=0.28), Metmax (p=0.7), or Metmean (p=0.32). One texture parameter, GLSZM-SZV (visually indicating that the 18F-FDG PET images of treated mice comprise uniformly sized clusters of different activity)) had significantly different means between the two groups of mice. Conclusions18F-FDG PET derived texture parameters, particularly GLSZM-SZV, may be valid biomarkers of tumour response to treatment with bevacizumab, before change in volume.

Aorta-atrial fistulas (AAF) are a rare but complex pathological condition. These fistulas are characterised by aberrant blood flow between the aorta and either atrium. In the present manuscript, we present a comprehensive overview of the clinical characteristics, formation and treatment of this condition. A literature review was conducted using PubMed. Aorta-Atrial Fistula was used as the primary search term. The clinical presentation of AAF encompasses a wide range of signs and symptoms of heart failure including dyspnoea, chest pain, palpitations, fatigue, weakness coughing or oedema. Causes of fistulas can be congenital or acquired, whilst diagnosis is normally achieved via echocardiography or MRI. Due to the low incidence of AAF, no clinical trials have been performed in AAF patients and treatment strategies are based on expert opinion and consensus amongst the treating physicians. Uncorrected AAF may continue to impose a risk of progression to overt heart failure. The repair of an AAF can either be surgical or percutaneous. AAF is a relatively rare but very serious condition. Clinicians should consider the possibility of AAF, when a new continuous cardiac murmur occurs, especially in patients with a history of cardiac surgery or with signs of heart failure. Closure of the AAF fistula tract is generally recommended. Further studies are required to define optimal therapeutic strategies, but these are hindered by the rarity of the occurrence of this disorder.

After mastectomy, breast reconstruction is increasingly performed using autologous tissue with the aim of improving quality of life. During this procedure, autologous tissue is excised, relocated, and reattached using microvascular anastomoses at the site of the extirpated breast. The period during which the tissue is ex vivo may allow genetic modification without any systemic exposure to the vector. Could such access permit delivery of therapeutic agents using the tissue flap as a vehicle? Such delivery may be more targeted and oncologically efficient than systemic therapy, and avoid systemic complications. The cytokine IFNγ has antitumor effects, and systemic toxicity could be circumvented by localized delivery of the IFNγ gene via gene therapy to autologous tissue used for breast reconstruction, which then releases IFNγ and exerts antitumor effects. In a rat model of loco-regional recurrence (LRR) with MADB-106-Luc and MAD-MB-231-Luc breast cancer cells, autologous tissue was transduced ex vivo with an adeno-associated viral vector encoding IFNγ. The “Therapeutic Reconstruction” released IFNγ at the LRR site and eliminated cancer cells, significantly decreased tumor burden, and increased survival compared with sham reconstruction (P

We present a simple solution to address—at the same time—the issue of spinal perfusion, overload on the left ventricle, and brain perfusion during complex distal arch and descending aortic surgery. It is a modification of a passive Gott shunt that includes an extra 10-mm tube interposed between the side port of the ascending aorta cannula and the left subclavian artery. This technique may represent an extra option for surgeons during complex aortic surgery to maintain satisfactory distal perfusion, to reduce the cardiac load, and to provide adequate perfusion to the brain. Keywords: Aorta, Aortic arch, Aneurysm, Shunt, Perfusion

Introduction\ud Uptake of preventive therapies for breast cancer is low. We examined whether women at increased risk of breast cancer can be categorized into groups with similar medication beliefs, and whether belief group membership was prospectively associated with uptake of preventive therapy.\ud \ud Patients and Methods\ud Women (n = 732) attending an appointment to discuss breast cancer risk were approached; 408 (55.7%) completed the Beliefs About Medicines and the Perceived Sensitivity to Medicines questionnaires. Uptake of tamoxifen at 3 months was reported in 258 (63.2%). The optimal number of belief groups were identified using latent profile analysis.\ud \ud Results\ud Uptake of tamoxifen was 14.7% (38/258). One in 5 women (19.4%; 78/402) reported a strong need for tamoxifen. The model fit statistics supported a 2-group model. Both groups held weak beliefs about their need for tamoxifen for current and future health. Group 2 (38%; 154/406 of the sample) reported stronger concerns about tamoxifen and medicines in general, and stronger perceived sensitivity to the negative effects of medicines compared with group 1 (62%; 252/406). Women with low necessity and lower concerns (group 1) were more likely to initiate tamoxifen (18.3%; 33/180) than those with low necessity and higher concerns (group 2) (6.4%; 5/78). After adjusting for demographic and clinical factors, the odds ratio was 3.37 (95% confidence interval, 1.08-10.51; P = .036).\ud \ud Conclusion\ud Uptake of breast cancer preventive therapy was low. A subgroup of women reported low need for preventive therapy and strong medication concerns. These women were less likely to initiate tamoxifen. Medication beliefs are targets for supporting informed decision-making.

The use of targeted intraoperative radiotherapy (TARGIT-IORT) as a tumour bed boost during breast-conserving surgery (BCS) for breast cancer has been reported since 1998. We present its use in patients undergoing breast conservation following neoadjuvant therapy (NACT). In this retrospective study involving 116 patients after NACT we compared outcomes of 61 patients who received a tumour bed boost with IORT during lumpectomy versus 55 patients treated in the previous 13 months with external (EBRT) boost. All patients received whole breast radiotherapy. Local recurrence-free survival (LRFS), disease-free survival (DFS), distant disease-free survival (DDFS), breast cancer mortality (BCM), non-breast cancer mortality (NBCM) and overall mortality (OS) were compared. Median follow up was 49 months. The differences in LRFS, DFS and BCM were not statistically significant. The 5‑year Kaplan–Meier estimate of OS was significantly better by 15% with IORT: IORT 2 events (96.7%, 95%CI 87.5–99.2), EBRT 9 events (81.7%, 95%CI 67.6–90.1), hazard ratio (HR) 0.19 (0.04–0.87), log rank p = 0.016, mainly due to a reduction of 10.1% in NBCM: IORT 100%, EBRT 89.9% (77.3–95.7), HR (not calculable), log rank p = 0.015. The DDFS was as follows: IORT 3 events (95.1%, 85.5–98.4), EBRT 12 events (69.0%, 49.1–82.4), HR 0.23 (0.06–0.80), log rank p = 0.012. IORT during lumpectomy after neoadjuvant chemotherapy as a tumour bed boost appears to give results that are not worse than external beam radiotherapy boost. These data give further support to the inclusion of such patients in the TARGIT-B (boost) randomised trial that is testing whether IORT boost is superior to EBRT boost.

Age estimation is a sub discipline of forensic odontology which plays an important part in every identification process, especially when information related to the deceased is unavailable. The aim of this study was to evaluate the accuracy of Demirjian’s Dental Age Estimation technique, with the help of Ortho-Pantomo-Graphs (OPG) in 50 children. 50 OPGs of children in the age group of 6-16 years were randomly selected and a cross-sectional retrospective study was conducted. Age estimation was done by the method given by Demirjian and two tailed test of the data was carried out. A significantly high difference was observed in the estimated and chronologic ages in the age group of 13-16 years than in 6-12 years. Demirjian’s original method, using seven mandibular teeth is an accurate method of age estimation in children especially of the younger age group (6-12 years of age).

Background: The Breast Cancer Campaign Gap analysis (2013) established breast cancer research priorities without specific focus on surgical research nor the role of surgeons. The majority of breast cancer patients encounter a surgeon at diagnosis or during treatment, thus surgical involvement in design and delivery of high-quality research to improve patient care is critical. This review aims to identify opportunities and priorities for breast surgical research to complement the previous gap analysis. Methods: Research-active breast surgeons met and identified topic areas for breast surgical research which mapped to the patient pathway. These included diagnosis, neoadjuvant treatment, surgery, adjuvant therapy and special groups (e.g. risk-reducing surgery). Section leads were identified based on research interests with invited input from experts in specific areas, supported by consultation with the Association of Breast Surgery (ABS) membership and Independent Cancer Patients’ Voice (ICPV). The document was iteratively modified until participants were satisfied that key priorities for surgical research were clear. Results: Key research gaps were identified for each topic area including: (1) issues surrounding overdiagnosis and treatment; (2) optimising selection for neoadjuvant therapies and subsequent surgery; (3) reducing re-operation rates for breast conserving surgery; (4) generating evidence for the clinical and cost-effectiveness of breast reconstruction and mechanisms for evaluating novel interventions; (5) determining optimal axillary management, especially post-neoadjuvant treatment; (6) defining and standardising indications for risk-reducing surgery. Strategies for resolving these knowledge gaps are proposed. Conclusions: Surgeons are ideally placed for a central role in breast cancer research and should foster a culture of engagement and participation in research to benefit patients and the NHS. Development of infrastructure and surgical research capacity together with appropriate allocation of research funding will be needed to successfully address the key clinical and translational research gaps highlighted in this analysis within the next two decades.

© 2018 Elsevier Ltd The 2013 Breast Cancer Campaign gap analysis established breast cancer research priorities without a specific focus on surgical research or the role of surgeons on breast cancer research. This Review aims to identify opportunities and priorities for research in breast surgery to complement the 2013 gap analysis. To identify these goals, research-active breast surgeons met and identified areas for breast surgery research that mapped to the patient pathway. Areas included diagnosis, neoadjuvant treatment, surgery, adjuvant therapy, and attention to special groups (eg, those receiving risk-reducing surgery). Section leads were identified based on research interests, with invited input from experts in specific areas, supported by consultation with members of the Association of Breast Surgery and Independent Cancer Patients' Voice groups. The document was iteratively modified until participants were satisfied that key priorities for surgical research were clear. Key research gaps included issues surrounding overdiagnosis and treatment; optimising treatment options and their selection for neoadjuvant therapies and subsequent surgery; reducing rates of re-operations for breast-conserving surgery; generating evidence for clinical effectiveness and cost-effectiveness of breast reconstruction, and mechanisms for assessing novel interventions; establishing optimal axillary management, especially post-neoadjuvant treatment; and defining and standardising indications for risk-reducing surgery. We propose strategies for resolving these knowledge gaps. Surgeons are ideally placed for a central role in breast cancer research and should foster a culture of engagement and participation in research to benefit patients and health-care systems. Development of infrastructure and surgical research capacity, together with appropriate allocation of research funding, is needed to successfully address the key clinical and translational research gaps that are highlighted in this Review within the next two decades.

Previously we have shown, using a primary glioblastoma (GBM) cell model, that a subpopulation of innately radiation resistant (RR) GBM cells survive radiotherapy and form multinucleated and giant cells (MNGCs) by homotypic fusions. We also showed that MNGCs may cause relapse. Here, we set out to explore whether molecular characteristics of RR cells captured from patient-derived primary GBM cultures bear clinical relevance.Primary cultures were derived from 19 naive GBM tumor samples. RR cells generated from these cultures were characterized using various cell biological assays. We also collected clinicopathological data of the 19 patients and assessed associations with RR variables using Spearman's correlation test and with patient survival using Kaplan-Meier analysis. Significance was determined using a log-rank test.We found that SF2 (surviving fraction 2) values (p = 0.029), days of RR cell formation (p = 0.019) and percentage of giant cells (p = 0.034) in the RR population independently correlated with a poor patient survival. We also found that low ATM (Ataxia-telangiectasia mutated) expression levels in RR cells showed a significant (p = 0.002) negative correlation with SF2 values. A low ATM expression level in RR cells along with a high tumor volume was also found to negatively correlate with patient survival (p = 0.011). Finally, we found that the ATM expression levels in RR cells independently correlated with a poor patient survival (p = 0.014).Our data indicate that molecular features of innately radiation resistant GBM cells independently correlate with clinical outcome. Our study also highlights the relevance of using patient-derived primary GBM cultures for the characterization of RR cells that are otherwise inaccessible for analysis.