Mitchel Barry

Is valve choice a significant determinant of paravalular leak post-transcatheter aortic valve implantation? A systematic review and meta-analysis

OBJECTIVES Paravalvular regurgitation (PVR) following transcatheter aortic valve implantation (TAVI) is associated with poor survival. The two main valve delivery systems used to date differ significantly in both structure and deployment technique. The primary objective of this study was to perform a systematic review and meta-analysis of studies identifying PVR in patients post-TAVI using Medtronic CoreValve (MCV) and Edward Sapien (ES) valves in order to identify whether a significant difference exists between valve types. The secondary objective was to identify additional factors predisposing to PVR to provide an overview of the other associated considerations. METHODS A systematic review and meta-analysis of the current literature to identify PVR rate in patients with MCV and ES valves was performed. We also sought to examine other factors predisposing to PVR. RESULTS A total of 5910 patients were identified from 9 studies. PVR rates for MCV and ES were analysed. MCV was associated with a higher PVR rate of 15.75% [95% confidence interval (CI) 12.48-19.32] compared with ES 3.93% [95% CI 1.05-8.38]. We separately reviewed predisposing factors associated with PVR. A formal comparison of the MCV and ES valve leakage rates by mixed-effects meta-regression with a fixed-effect moderator variable for valve type (MCV or ES) suggested a statistically significant difference in leakage rate between the two valve types (P = 0.0002). CONCLUSIONS Unfavourable anatomical and pathological factors as well as valve choice have an impact on rates of PVR. Additionally, certain anatomical features dictate valve choice. A direct comparison of all the predisposing factors at this time is not possible and will require prospective multivariate analysis. There is, however, a significant difference in the PVR rates between valves based on the published observational data available to date. The ES valve associated with a lower incidence of PVR overall; therefore, we conclude that valve choice is indeed a significant determinant of PVR post-TAVI.

Is local anesthesia the optimum strategy in retrograde transcatheter aortic valve implantation? A systematic review and meta-analysis.

BACKGROUND Retrograde transcatheter aortic valve implantation (TAVI) can be performed under local anesthesia (LA) or general anesthesia (GA); however, a wide variation in practice exists. METHODS PubMed was searched between 2009 and 2013. Data were extracted from eligible studies. Random-effects meta-analysis was performed using DerSimonian Laird between-study variance. RESULTS There was no statistically significant difference identified between groups based on age or EuroSCORE. There was no statistically significant difference seen in all-cause mortality, or complication rates between groups. Mean procedural duration was 36 minutes shorter in the LA group (p = 0.001). There was increased vasopressor use in the GA group (odds ratio 3.92; p = 0.017). Mean hospital stay was 3.41 days shorter in the LA group (p = 0.018). CONCLUSION Results suggest that the use of LA for retrograde TAVI is feasible. There are several potential benefits associated, shorter procedural duration, and hospital stay with lower vasopressor requirements. Further studies and randomized trials are mandatory to confirm the presented findings and to identify those patients for whom LA would be appropriate.

An overview of triple negative breast cancer for surgical oncologists.

Triple negative breast cancers (TNBCs) represent a distinct subgroup of breast cancers with an immunohistochemical phenotype that is negative for oestrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2). The aim of this article is to provide a broad overview of recent developments in the diagnosis and management of TNBC for surgical oncologists. This overview discusses the subtypes of TNBC and the relationship between this type of breast cancer and the BRCA1 gene. In addition, the article explores recent advances in the treatment of TNBC from a surgical, radiation, and medical oncology point of view. Lastly, evolving therapeutic strategies that have potential to enhance outcomes for patients with TNBC are also discussed.

A meta-analysis of optimum plane placement and related morbidity in primary breast augmentation

Despite extensive clinical experience of breast implants, there is continued controversy regarding the optimum placement of the prosthesis. More importantly, there is insufficient data to accurately determine whether subglandular (SG) or submuscular (SM) placement of the prosthesis diminishes postoperative complications. A search of published trials (n = 34) examined complication rates following SG and SM implant placement was conducted. Pubmed (MEDLINE) database was used and the available data was then cross-referenced. Eligible trials (n = 6) were then reviewed and selected data extracted. Primary outcomes measured were postoperative haematoma, infection, capsular contracture and implant migration. 3603 patients were identified from relevant trials examining postoperative complication rates for both subglandular and submuscular implant planes. The submuscular implant plane was associated with a higher incidence of postoperative haematoma (OR 2.87, 95% CI, 1.44-6.11). The incidence of capsular contracture (OR 4.77) is more common when a subglandular plane is used. No significant difference was noted in the rate of postoperative infection (OR 1.20, 95% CI 0.57-2.58) or implant migration (OR 1.56, 95%CI 0.12-87.4) between the two groups. This meta-analysis confirms that subglandular augmentation results in lower short-term morbidity; however, submuscular placement appears to provide the best long-term outcome in terms of morbidity. In the absence of randomized controlled trials comparing these two techniques, this meta-analysis provides evidence to guide surgeons to achieve the best outcomes for their patients.

Enhancing the Adjuvant Treatment of Hormone Receptor Positive Breast Cancer

Abstract:  Aromatase inhibitors (AIs) are now regarded as the optimum hormonal therapy for postmenopausal women with hormone receptor positive breast cancer. However, it is unclear which of the currently available AIs offers patients the most effective and the best‐tolerated treatment strategy. We performed a systematic review and meta‐analysis of randomized‐controlled trials that compared AIs (as first‐line agents) with standard hormonal treatment in patients with breast cancer. The results suggest that letrozole offers a more favorable side‐effect profile particularly in terms of musculoskeletal adverse events. However, the available data suggests a small survival benefit from the use of anastrozole although patients treated with anastrozole appear to have a more favorable disease profile at study entry. Examination of survival data on adjuvant tamoxifen therapy from these trials supports this observation.

Supporting trials for primary tumor resection in stage IV breast cancer is paramount.

A key motivation behind publishing our meta-analysis to determine whether surgical resection of the primary tumor in the setting of stage IV breast cancer affects survival was to reassure clinicians and their patients that entering patients into the one of the ongoing six randomized trials—or indeed into the prospective registry study led by T. A. King—was safe and would not compromise patient care. Failure to accrue the appropriate number of patients can be detrimental to any randomized trial, and therefore some level of evidence, albeit biased and with recognized limitations, is required to support trial accrual. In addition to the published meta-analyses, an editorial by Seema Khan accompanies our study. Khan raises a number of important questions, though offers a number of conflicting comments. Firstly, Khan is correct when she states, ‘‘Authors must be challenged when they state in the abstract...what they cannot support.’’ Khan describes the ‘‘flood of publications rather than data on this topic.’’ While searching through this flood, I discovered a singlecenter retrospective review of 47 patients with stage IV breast cancer who underwent resection of the primary tumor. The authors demonstrated a survival advantage in this small group of 47 patients, and in the conclusion of the abstract, they state, ‘‘These data support the notion that improved local control may play a role in improving outcomes in women with stage IV breast cancer and resection of the in-breast tumors can help to achieve this.’’ Khan is the senior author on this 2008 publication and references this article in the recent editorial. In our abstract, we state, ‘‘In the absence of robust evidence, this meta-analysis provides evidence base for primary resection in the setting of stage IV breast cancer for appropriately selected patients.’’ Patients can be appropriately selected through a multidisciplinary discussion and consensus combined with sound clinical judgment and a patient who has been fully informed of the risks, benefits, and alternatives. The editorial also questions our methodology: ‘‘Notably, Harris et al. do not tell us how much between-study heterogeneity they observed and whether a random or a fixedeffects model was used.’’ In performing the meta-analysis, we observed significant cross-trial heterogeneity; hence, a random-effects model was applied. In 2011, Khan wrote, ‘‘Retrospective data on more than 30,000 women from North America and Europe have now been published, showing robust association between surgery...for the primary tumor and prolonged survival’’ in patients with stage IV breast cancer. In 2013, the title of her editorial is ‘‘Surgery for the intact primary and stage IV breast cancer...lacking ‘robust evidence.’’’ The editorial highlights that ‘‘this is the fourth analysis of the same data’’ and cautions readers that this is the ‘‘same biased data in new garb.’’ Our current meta-analysis was accepted pending corrections in November 2012. At this time, no other meta-analysis of these data was published. In December 2012, a similar meta-analysis was published by Petrelli and Barni. Neither the authors nor the editorial board could have been aware of this during the review process. Furthermore, this is not the fourth analyzes of the same data. A systematic review and a meta-analysis are very different scientific entities. However, the most concerning remark in this editorial is, ‘‘We cannot in good conscience offer resection of the intact primary unless it progresses while distant disease is well controlled.’’ This comment may be detrimental in supporting the ongoing randomized trials. In 2011, in Society of Surgical Oncology 2013

Gene-expression profiling in breast cancer: bespoke cancer therapy or more fiction than science?

Breast cancer is the most common life threatening malignancy in women. Despite advances in molecular therapeutics, many patients with apparently early stage and curable disease still develop progressive and fatal systemic disease. Haffty et al. [1] demonstrated that despite conservative surgery and radiation followed by administration of chemotherapy in early-stage (T1 tumours) breast cancer patients, the distant metastasis-free survival rate was 71% at 5 years in patients with triple negative disease and 83% at 5 years in non-triple negative. These patients have potentially been under-staged by conventional staging, and therefore may not have received optimum therapy due to their misleading clinical disease profile. Conversely, patients receiving systemic therapy may not derive any additional benefit. Breast cancer is an intricate genetic milieu characterised by numerous molecular alterations that prevents standardising therapeutic strategies to all patients. Until recently, it has been difficult to accurately profile and predict the biological properties and clinical behaviour of breast tumours, however, with the development of DNA microarray technology, it is now possible to analyse the RNA expression of several thousands of genes simultaneously. The clinical application of this technology has the potential to signal a paradigm shift in patient selection for systemic therapy. First, it provided a new molecular classification of breast cancer. This classification was proposed by Perou et al. [2], and subdivided breast cancers into four classes. Luminal-A cancers are ER-positive and mostly low grade. Luminal-B cancers are also ER-positive but tend to be high grade. Basal-like cancers are triple negative and Her-2-like cancers are Her-2 positive and usually ER negative. Currently, there are a number of validated commercially available multigene assays that identify expression of distinct sets of genes in breast cancer: Mammaprint (Agendia), Oncotype DX (Genomic Health), MapQuant and H/I (AvariaDX) (see Table 1 for comparison of assays). Mammaprint uses DNA microarray technology, whereas Oncotype DX and H/I use real time PCR based assays. These assays accurately predict the potential for disease recurrence and enhance patient selection for chemotherapeutic strategies. Mammaprint uses a 70-gene predictor and is involved in the MINDACT (Microarray In Node negative Disease may Avoid ChemoTherapy) trial [3]. The objective is to administer chemotherapy to patients deemed at high risk of recurrence, and hormonal therapy only to low risk patients, as determined by the Mammaprint gene profile. Having recruited large numbers of patients who are stratified based on the clinical and pathological risks, it is hoped that this study will provide important information regarding the prognostic capabilities of the Mammaprint test and also validate its use in identifying women associated with improved survival. Previously, Buyse et al. [4] demonstrated that Mammaprint outperformed Adjuvant Online in predicting survival in an independent group of patients. Unfortunately, however, a major disadvantage of Mammaprint is that it requires fresh tissue for analysis, which may make its clinical integration difficult. The Oncotype DX and H/I assay, however, can use archival tissue (tissue from original biopsy) and may be more readily applied to the clinical setting. By analysing the expression of 21 known genes, Oncotype DX accurately determined the prognostic outcome in hormone receptor positive cancers post adjuvant tamoxifen in a retrospective cohort of 668 M. Barry M. R. Kell (&) Eccles Breast Screening Unit, Mater Misericordiae University Hospital, Eccles St, Dublin 7, Ireland e-mail: malcolm.kell@breastcheck.ie

Influence of tumour biology on the surgical management of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) accounts for 15–20 per cent of all breast cancers. TNBCs are characterized by lack of expression of oestrogen, progesterone and epidermal growth factor type 2 (Her-2) receptors. They have a poor prognosis owing to the lack of effective targeted therapies1. TNBCs are usually highgrade, behave aggressively and, in the absence of a biological target, require definitive local control. There is a current lack of evidence to indicate whether the surgical management of TNBC should be different from that of receptor-positive cancers. Six randomized clinical trials have shown that mastectomy and wide local excision to clear margins combined with whole-breast radiation are equally effective in terms of long-term survival2. Unfortunately, there were no receptor data provided in these studies so it is impossible to determine what proportion of local recurrences in the breast-conserved cohorts might have been TNBCs. The evidence that breast conservation is safe for patients with TNBC is inconclusive. One early study found no significant difference in local control in patients undergoing breast-conserving surgery between TNBCs (117) and non-TNBCs (365), with a median follow-up of 7·9 years3. However, a recent systematic review of locoregional recurrence (LRR) by receptor phenotype, involving 15 studies and 7174 patients undergoing breast conservation, demonstrated that patients with luminal subtype tumours (oestrogen receptor/progesterone receptor-positive) had a lower risk of LRR than those with TNBCs (relative risk 0·38, 95 per cent confidence interval 0·23 to 0·61)4. A retrospective analysis of 768 patients with T1–T2 N0 TNBC demonstrated a 5-year LRR-free survival of 96 per cent in patients undergoing breast conservation, compared with 90 per cent in those undergoing mastectomy without postmastectomy irradiation5. This probably reflects selection bias as 33 per cent of the breast conservation group had a T2 tumour compared with 47 per cent of the mastectomy group. More importantly, the LRR was the same when radiotherapy followed either mastectomy or breast conservation, suggesting that surgery is not the critical factor in local control of TNBC but radiotherapy is essential. The current American Society of Clinical Oncology postmastectomy radiation guidelines are based on tumour size and nodal disease, and do not consider the biology of the primary tumour6. The use of neoadjuvant chemotherapy should also be considered, particularly if the disease is locally advanced or likely to require a mastectomy. Subtypes of TNBC, which have yet to be fully characterized, appear to be more chemosensitive and for these patients a pathological complete response (pCR) is a favourable prognostic marker7. Numerous studies have confirmed this favourable response of TNBCs to neoadjuvant chemotherapy compared with non-TNBCs, and this may be used to change the required procedure from mastectomy to a more conservative procedure. Patients with TNBC who achieve a pCR have equivalent survival to those with hormone receptor-positive cancers; however, the overall prognosis remains poor when there is evidence of residual disease in the resected specimen, irrespective of operation type7. BRCA1 testing should be performed in women under 40 years of age who present with a TNBC, with or without a family history of breast or ovarian cancer, as it will radically alter the surgical management8. A discussion with a known mutation carrier should include the risks, benefits and alternatives to bilateral mastectomy and oophorectomy, and the limitations of surveillance programmes in this setting. If genetic testing is not readily available, consideration should be given to referring such patients to a centre that provides this service in a timely manner. Alternatively, if BRCA testing is not readily available, neoadjuvant chemotherapy may be used while waiting for genetic test results. Management of the axilla in TNBC is also controversial. The recent American College of Surgeons Oncology Group trial (Z0011) demonstrated that axillary lymph node dissection failed to confer any oncological benefit among patients with breast cancer without clinically or radiologically apparent axillary metastases, but who had a positive sentinel node, undergoing breast-conserving surgery with radiotherapy9. Sixty-seven patients in the study (17 per cent) had oestrogen receptor-negative disease and Her-2 receptor data was not available, so