Clinicopathological and prognostic significance of programmed cell death ligand 1 expression in patients diagnosed with breast cancer: meta-analysis.

BACKGROUND: Uncertainty exists regarding the clinical relevance of programmed cell death ligand 1 (PD-L1) expression in breast cancer. METHODS: A systematic review was performed in accordance with PRISMA guidelines. Observational studies that compared high versus low expression of PD-L1 on breast cancer cells were identified. Log hazard ratios (HRs) for disease-free and overall survival and their standard errors were calculated from Kaplan-Meier curves or Cox regression analyses, and pooled using the inverse-variance method. Dichotomous variables were pooled as odds ratios (ORs) using the Mantel-Haenszel method. RESULTS: Sixty-five studies with 19 870 patients were included; 14 404 patients were classified as having low and 4975 high PD-L1 expression. High PD-L1 was associated with achieving a pathological complete response following neoadjuvant chemotherapy (OR 3.30, 95 per cent confidence interval 1.19 to 9.16; P < 0.01; I2 = 85 per cent). Low PD-L1 expression was associated with human epidermal growth factor receptor 2 (OR 3.98, 1.81 to 8.75; P < 0.001; I2 = 96 per cent) and luminal (OR 14.93, 6.46 to 34.51; P < 0.001; I2 = 99 per cent) breast cancer subtypes. Those with low PD-L1 had favourable overall survival rates (HR 1.30, 1.05 to 1.61; P = 0.02; I2 = 85 per cent). CONCLUSION: Breast cancers with high PD-L1 expression are associated with aggressive clinicopathological and immunohistochemical characteristics and are more likely to achieve a pathological complete response following neoadjuvant chemotherapy. These breast cancers are, however, associated with worse overall survival outcomes.

Association of BMI with Clinicopathological Features of Papillary Thyroid Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: Papillary thyroid cancer (PTC) is the most common subtype of thyroid cancer. The incidence of PTC is rising in tandem with an obesity epidemic. Associations have been demonstrated between increased body mass index (BMI) and worse oncological outcomes in a number of malignancies. However, research on this topic in PTC to date has been inconsistent, often due to limited data. This study aimed to measure the association between BMI and potentially adverse clinicopathological features of PTC. METHODS: A meta-analysis of studies reporting outcomes after surgical treatment of PTC was performed. PubMed, Embase and the Cochrane Library were searched systematically to identify studies which provided data on BMI and clinicopathologic features of PTC. Relevant data were extracted and synthesis performed using adjusted odds ratios where available and crude values when not. Data were analysed by inverse variance using random and fixed effects models. RESULTS: Data on 35,237 patients from 15 studies met the criteria for inclusion. Obesity was associated with larger tumour size (MD = 0.17 cm [0.05, 0.29]), increased rates of multifocality (OR = 1.41 [1.16, 1.70]), extrathyroidal extension (OR = 1.70 [1.39, 2.07]) and nodal spread (OR = 1.18 [1.07, 1.30]). Associations were more pronounced as BMI increased. There was no association between BMI and bilaterality, vascular invasion or metastatic spread. CONCLUSION: Increased BMI is significantly associated with multiple potentially adverse features of PTC. The effect on long-term oncological outcomes requires further evaluation.

Quantifying Argonaute 2 (Ago2) expression to stratify breast cancer.

BACKGROUND: Argonaute-2 (Ago2) is an essential component of microRNA biogenesis implicated in tumourigenesis. However Ago2 expression and localisation in breast cancer remains undetermined. The aim was to define Ago2 expression (mRNA and protein) and localisation in breast cancer, and investigate associations with clinicopathological details. METHODS: Ago2 protein was stained in breast cancer cell lines and tissue microarrays (TMAs), with intensity and localization assessed. Staining intensity was correlated with clinicopathological details. Using independent databases, Ago2 mRNA expression and gene alterations in breast cancer were investigated. RESULTS: In the breast cancer TMAs, 4 distinct staining intensities were observed (Negative, Weak, Moderate, Strong), with 64.2% of samples stained weak or negatively for Ago2 protein. An association was found between strong Ago2 staining and, the Her2 positive or basal subtypes, and between Ago2 intensity and receptor status (Estrogen or Progesterone). In tumours Ago2 mRNA expression correlated with reduced relapse free survival. Conversely, Ago2 mRNA was expressed significantly lower in SK-BR-3 (HER2 positive) and BT-20 (Basal/Triple negative) cell lines. Interestingly, high levels of Ago2 gene amplification (10-27%) were observed in breast cancer across multiple patient datasets. Importantly, knowledge of Ago2 expression improves predictions of breast cancer subtype by 20%, ER status by 15.7% and PR status by 17.5%. CONCLUSIONS: Quantification of Ago2 improves the stratification of breast cancer and suggests a differential role for Ago2 in breast cancer subtypes, based on levels and cellular localisation. Further investigation of the mechanisms affecting Ago2 dysregulation will reveal insights into the molecular differences underpinning breast cancer subtypes.

Role of micro-RNAs in breast cancer surgery.

BACKGROUND: The management of breast cancer has changed dramatically in the molecular era. Micro-RNAs can contribute to multiple facets of cancer surgery. METHODS: This narrative review, based on years of research on the role of micro-RNAs, focused on the potential of these small, robust RNAs to influence all aspects of breast cancer surgery. RESULTS: Micro-RNAs have a potential role as biomarkers in the diagnosis, prognosis and evaluation of response to therapy in breast cancer. They may also contribute to future therapeutic strategies. CONCLUSION: The molecular era has changed understanding of cancer. Micro-RNAs have the potential for use in personalized cancer strategies.

Meta-analysis of the diagnostic accuracy of ultrasound-guided fine-needle aspiration and core needle biopsy in diagnosing axillary lymph node metastasis.

BACKGROUND: Axillary lymph node status remains a significant prognostic indicator in breast cancer. Here, the diagnostic accuracy of ultrasound-guided fine-needle aspiration (US-FNA) and ultrasound-guided core needle biopsy (US-CNB) in axillary staging was compared. METHODS: A comprehensive search was undertaken of all published studies comparing the diagnostic accuracy of US-CNB and US-FNA of axillary lymph nodes in breast cancer. Studies were included if raw data were available on the diagnostic performance of both US-FNA and US-CNB, and compared with final histology results. Relevant data were extracted from each study for systematic review. Meta-analysis was performed using a random-effects model. The pooled sensitivity and specificity of US-FNA and US-CNB were obtained using a bivariable model. Summary receiver operating characteristic (ROC) graphs were created to confirm diagnostic accuracy. RESULTS: Data on a total of 1353 patients from six studies met the inclusion criteria and were included in the final analysis. US-CNB was superior to US-FNA in diagnosing axillary nodal metastases: sensitivity 88 (95 per cent c.i. 84 to 91) versus 74 (70 to 78) per cent respectively. Both US-CNB and US-FNA had a high specificity of 100 per cent. Reported complication rates were significantly higher for US-CNB compared with US-FNA (7·1 versus 1·3 per cent; P < 0·001). Conversely, the requirement for repeat diagnostic procedures was significantly greater for US-FNA (4·0 versus 0·5 per cent; P < 0·001). CONCLUSION: US-CNB is a superior diagnostic technique to US-FNA for axillary staging in breast cancer.

Correction to: Breast cancer subtype discordance: impact on post-recurrence survival and potential treatment options.

It has been highlighted that the original manuscript [1] contains a typesetting error regarding the authorship.

Breast cancer subtype discordance: impact on post-recurrence survival and potential treatment options.

BACKGROUND: Recent studies have shown that breast cancer subtype can change from the primary tumour to the recurrence. Discordance between primary and recurrent breast cancer has implications for further treatment and ultimately prognosis. The aim of the study was to determine the rate of change between primary and recurrence of breast cancer and to assess the impact of these changes on survival and potential treatment options. METHODS: Patient demographics were collected on those who underwent surgery for breast cancer between 2001 and 2014 and had a recurrence with biopsy results and pathology scoring of both the primary and recurrence. RESULTS: One hundred thirty two consecutive patients were included. There were 31 (23.5%) changes in subtype. Discordance occurred most frequently in luminal A breast cancer (n = 20), followed by triple negative (n = 4), luminal B (n = 3) and HER2 (n = 3). Patients who changed from luminal A to triple negative (n = 18) had a significantly worse post-recurrence survival (p < 0.05) with overall survival approaching significance (p = 0.064) compared to concordant luminal A cases (n = 46). Overall receptor discordance rates were: estrogen receptor 20.4% (n = 27), progesterone receptor 37.7% (n = 50) and HER2 3% (n = 4). Loss of estrogen receptor and progesterone receptor was more common than gain (21 vs. 6 (p = 0.04) and 44 vs. 6 (p = 0.01) respectively). Nine patients (6.8%) gained receptor status potentially impacting treatment options. CONCLUSION: Discordance in subtype and receptor status occurs between primary and recurrent breast cancer, ultimately affecting survival and potentially impacting treatment options.

Prospective comparison of outcome after treatment for triple-negative and non-triple-negative breast cancer.

INTRODUCTION: Triple-negative breast cancers (TNBC) are associated with a poor prognosis owing to an aggressive phenotype. We aimed to carry out a prospective study comparing management strategies and response to therapy in TNBC and non-TNBC patients. METHODS: Data were obtained from a prospectively maintained database of patients treated for breast cancer. RESULTS: A total of 142 TNBC and 142 age-, stage- and NPI-matched non-TNBC patients were treated. The difference in overall survival between the 2 groups was statistically significant (77% of TNBC patients alive at a mean follow-up of 32 months, versus 92% of non-TNBC patients at a mean follow-up of 38 months, P = 0.0 Log rank test). This survival difference was found to be independent of NPI (P = 0.0 Log rank test). Locoregional recurrence rates were similar between TNBC patients who were treated with wide local excision versus mastectomy (P = 0.449 Log rank test). A significant difference in survival was noted between TNBC patients who responded differentially to neoadjuvant chemotherapy (P = 0.035 Log rank test). CONCLUSION: Patients with TNBC have adverse outcomes despite aggressive treatment. The development of effective targeted therapies is essential for this breast cancer subtype.

Influence of complications following immediate breast reconstruction on breast cancer recurrence rates.

BACKGROUND: The rate of immediate breast reconstruction is rising. Postoperative infections are more frequent in patients who undergo reconstruction. The inflammatory response to a postoperative infection can increase the risk of tumour recurrence in other forms of cancer through the release of proinflammatory mediators. The aim of this study was to assess the relationship between complications and breast cancer recurrence in patients undergoing immediate reconstruction. METHODS: This was a review of a prospectively maintained database of all patients who had immediate breast reconstruction between 2004 and 2009 at Galway University Hospital, a tertiary breast cancer referral centre serving the west of Ireland. All patients had a minimum follow-up of 5 years. Outcomes assessed included the development of wound complications and breast cancer recurrence. The data were evaluated by univariable and multivariable Cox regression analysis. RESULTS: A total of 229 patients who underwent immediate reconstruction were identified. The overall 5-year recurrence-free survival rate was 85·6 per cent. Fifty-three patients (23·1 per cent) had wound complications, of whom 44 (19·2 per cent) developed a wound infection. There was a significantly greater risk of developing systemic recurrence among patients who experienced a postoperative wound complication compared with those without a complication (hazard ratio 4·94, 95 per cent c.i. 2·72 to 8·95; P < 0·001). This remained significant after adjusting for Nottingham Prognostic Index group in the multivariable analysis. The 5-year recurrence-free survival rate for patients who had a wound complication was 64 per cent, compared with 89·2 per cent in patients without a complication (P < 0·001). CONCLUSION: This study has demonstrated that wound complications after immediate breast reconstructive surgery have significant implications for patients with breast cancer. Strategies are required to minimize the risk of postoperative wound complications in patients with breast cancer undergoing immediate reconstruction.

Standards in Operation Notes--Is It Time to Re-Emphasise Their Importance?

Guidelines exist for operation notes from the Royal College of Surgeons of England but compliance has been shown to be variable. The authors performed a closed loop audit of compliance with RCS standards in an Irish Plastic Surgery department. Thirty random operation notes were selected from a conserved pool of authors--before and after an educational intervention to increase awareness of the RCS guidelines. Following education, improvements were noted but also deteriorations--time increased from 12 (40%) to 16 (53%), emergency/elective status from none (0%) to 11 (36%), and operative diagnosis from seven (23%) to 21 (70%). However notably among the findings, surgeon's name decreased from 30 (100%) to 26 (86%), findings from 27 (90%) to 21 (53%) and tissue altered from 27 (90%) to 20 (66%). As some specialities are developing operation note standards specific to individual procedures, the findings are compared with previous similar published work.

A meta-analysis to determine the oncological implications of conversion in laparoscopic colorectal cancer surgery.

AIM: Laparoscopic colon and rectal cancer surgery is oncologically equivalent to open resection, but the impact of conversion is undetermined. The aim of this study was to assess the oncological outcome and predictive factors associated with conversion. METHOD: A comprehensive search for published studies examining the associated factors and outcome of conversion from laparoscopic to open colorectal cancer resection was performed adhering to PRISMA (Preferred Reporting Items in Systematic Reviews and Meta-analyses) guidelines. Only randomized control trials and prospective studies were included. Each study was reviewed and the data extracted. Random effects methods were used to combine data. RESULTS: Fifteen studies, including 5293 patients, met the inclusion criteria. Of these 4391 patients had a completed laparoscopic resection and 902 were converted to an open resection. The average conversion rate of the studies was 17.9 ± 10.1%. Meta-analysis showed completed laparoscopic surgery favoured lower 30-day mortality (OR 0.134, 95% CI 0.047-0.385, P < 0.0001), lower long-term disease recurrence (OR 0.634, 95% CI 0.421-0.701, P < 0.023) and lower overall mortality (OR 0.512, 95% CI 0.417-0.629, P < 0.0001). Factors negatively associated with completion of laparoscopic surgery were male gender (P = 0.011), rectal tumour (P = 0.017), T3/T4 tumour (P = 0.009) and node-positive disease (P = 0.009). Completed laparoscopic surgery was also associated with a lower body mass index (BMI; mean difference -0.93 kg/m(2) , P = 0.004). CONCLUSION: The results suggest that conversion from laparoscopic to open colorectal cancer resection is influenced by patient and tumour characteristics and is associated with an adverse perioperative outcome. Although confounding factors such as advanced tumour stage and elevated BMI are present, unsuccessful laparoscopic surgery appears to be associated with an adverse long-term oncological outcome.

Utilisation of Clinical Networks to Facilitate Elective Surgical Workload; A Preliminary Analysis.

Clinical networks have potential to increase elective surgical workload for benign conditions in non-cancer centres. The aims of this study were to determine outcomes for elective laparoscopic cholecystectomy in our unit and to evaluate early experience in managing benign surgical workload referred from the tertiary centre within our clinical network. An analysis of cholecystectomies performed at Mayo General Hospital was conducted (2003-2013). A review of elective procedures more recently referred from Galway University Hospital (GUH) waiting lists was also conducted. 1937 consecutive cholecystectomies were performed with an overall laparoscopic conversion rate of 1.7% (33/1875). The total major complication rate was 0.93% (18/1937). 151 selected procedures originating from GUH have been performed since December 2013 without adverse events. Laparoscopic cholecystectomy can be performed in significant volume in the general hospital environment. This and other appropriate benign surgical procedures may be performed outside of tertiary units according to network agreements.

FGF receptor genes and breast cancer susceptibility: results from the Breast Cancer Association Consortium.

BACKGROUND: Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying genotyped single-nucleotide polymorphisms (SNPs) and imputed SNPs in FGFR1, FGFR3, FGFR4 and FGFRL1 in the Breast Cancer Association Consortium. METHODS: Data were combined from 49 studies, including 53 835 cases and 50 156 controls, of which 89 050 (46 450 cases and 42 600 controls) were of European ancestry, 12 893 (6269 cases and 6624 controls) of Asian and 2048 (1116 cases and 932 controls) of African ancestry. Associations with risk of breast cancer, overall and by disease sub-type, were assessed using unconditional logistic regression. RESULTS: Little evidence of association with breast cancer risk was observed for SNPs in the FGF receptor genes. The strongest evidence in European women was for rs743682 in FGFR3; the estimated per-allele odds ratio was 1.05 (95% confidence interval=1.02-1.09, P=0.0020), which is substantially lower than that observed for SNPs in FGFR2. CONCLUSION: Our results suggest that common variants in the other FGF receptors are not associated with risk of breast cancer to the degree observed for FGFR2.

Interns and their smartphones: use for clinical practice.

PURPOSE OF THE STUDY: Smartphone use among healthcare professionals has become widespread and will continue to grow in the coming years. STUDY DESIGN: In October 2012, a survey was distributed to 230 interns at two of the national intern training networks in the Republic of Ireland, asking how they used smartphones to carry out their clinical work. RESULTS: It was found that out of 108 interns (47.0% response rate, 108/230), 94.4% (102/108) owned a smartphone. Of those respondents who owned a smartphone, on at least a daily basis for the purposes of work, 83.3% (85/102) made or received phone calls, 87.2% (89/102) sent or received texts, and 41.2% (42/102) sent or received emails on their smartphone. A total of 52.9% (54/102) had used their smartphone to take a work related picture. The most commonly used app was the British National Formulary. It was used daily by 30.4% (31/102) of respondents with a smartphone. The most commonly used website was Wikipedia. It was accessed at least weekly by 38.2% (39/102) of respondents with a smartphone. CONCLUSIONS: Smartphones are used by the majority of interns on a daily basis in order to perform their job. As such, there is a need for guidance on how patient information can be safely secured and transmitted using smartphones, their appropriate use, and any restrictions on the use of these devices in certain clinical settings. For interns in particular, advice is needed on the credibility of medical apps and websites.

Follow-up arrangements for breast cancer patients; is it appropriate to transfer surveillance to general practitioners?

The aim of this study was to examine the evidence for hospital follow up of breast cancer survivors and to identify patient preferences for hospital or community follow-up. We surveyed General Practitioner attitudes towards community follow-up and quantified the incidence of new or recurrent cancers within a patient cohort to identify their primary symptoms and thus cancer detection in the community. A 22 item questionnaire was distributed to 101 breast cancer survivors from a cohort of 921 treated patients. A 9 item questionnaire was distributed to 81 General Practitioners. Patients are reassured by hospital outpatient appointments, n=63 (74%) but have high levels of confidence in General Practitioner follow-up, n=57 (67%). General Practitioners are equally divided regarding their support for the transfer of follow-up (51%, 49%). Ten of the 14 new cancer episodes were associated with obvious clinical signs (p < 0.05). The proposed transfer of follow-up for patients to general practice by the national cancer control programme is appropriate.

From sabers to spikes: A newfangled reconstruction of the ancient, giant, sexually dimorphic Pacific salmon, †Oncorhynchus rastrosus (SALMONINAE: SALMONINI).

The impressive †Oncorhynchus rastrosus of the Pacific Northwest's Miocene and Pliocene eras was the largest salmonid ever to live. It sported a hypertrophied premaxilla with a pair of enlarged teeth which the original describers reconstructed as projecting ventrally into the mouth, leading them to assign the species to "Smilodonichthys," a genus now in synonymy. Through CT reconstruction of the holotype and newly collected specimens, we demonstrate that the famed teeth projected laterally like tusks, not ventrally like sabers or fangs. We also expand the original description to characterize sexual dimorphism in mature, breeding individuals. Male and female †Oncorhynchus rastrosus differ in the form of the vomer, rostro-dermethmoid-supraethmoid, and dentary, much as do other extant species of Oncorhynchus. Male specimens possess a more elongate vomer than do females, and female vomers have concave ventral surfaces and prominent median dorsal keels. The dentary of females has no evidence of a kype, though some specimens of †O. rastrosus have a non-uniform density mesial to the tooth bed, which we interpret as a male kype. Unlike extant Oncorhynchus, male and female †O. rastrosus do not differ in premaxilla shape. Because male and females possess hypertrophied premaxillae and lateral premaxillary spikes, the former common name "Sabertoothed Salmon" no longer reflects our understanding of the species' morphology. Accordingly, we redub †O. rastrosus the Spike-Toothed Salmon and postulate that its spikes were multifunctional, serving as defense against predators, in agonism against conspecifics, and as a practical aid to nest construction.

Systemic mirnas as potential biomarkers for malignancy.

MiRNAs are a class of short, endogenous, single-stranded RNA molecules that play a role in the regulation of gene expression. They have been shown to modulate a number of cellular processes including cell differentiation, growth and apoptosis and as a result have been implicated in carcinogenesis. They are detectable in tumour tissue, and altered expression levels have been identified in various cancer types. Of interest, miRNAs have recently been detected and identified to be dysregulated in the circulation of patients with breast cancer. The fact that a minimally invasive test can distinguish the presence or absence of disease illustrates the immense potential these molecules hold as predictive markers. This review serves to identify those systemic miRNAs that are upregulated or downregulated in malignancy and how treatment impacts on their circulating levels. In addition, this review questions the source of these small molecules in the bloodstream and how they may possibly play a role in the future detection of cancer as either prognostic or predictive markers.

Circulating miR-34a levels are reduced in colorectal cancer.

INTRODUCTION: MicroRNAs (miRNAs) are small, non-coding RNA segments that regulate gene expression via post-transcriptional inhibition and have roles in cell differentiation, proliferation, and apoptosis. Expression differs between tumor and normal tissue in several malignancies. Most work has focused on tissue and cell expression with few reports of circulating miRNAs in colorectal cancer. Available biomarkers for colorectal cancer have limited sensitivity and specificity, thus there is a need for new markers. AIMS: This study aimed to identify miRNAs that are differentially expressed in the blood of colorectal cancer patients compared to controls and to establish if this is specific to colorectal cancer and thus could be utilized as potential tumor markers. METHODS: Blood samples were collected from 63 colorectal cancer patients and 45 controls. Expression of 7 target miRNAs (miR-143, miR-145, miR-21, miR-30a-3p, miR-31, miR-34a, and miR-92) was measured using RQ-PCR. Results were correlated with clinicopathological data and analyzed. Analysis of differentially expressed circulating miRNAs was expanded to include 62 patients with prostate, renal, breast, and melanoma cancers. RESULTS: Analysis of the relative quantification of the target miRNAs showed significantly reduced expression (P = 0.004) of miR-34a in colorectal cancer. MiR-34a was also significantly reduced in breast cancer (P = 0.019). CONCLUSION: This study demonstrates significantly reduced expression of circulating miR-34a in colorectal and breast cancer. This may have future application as part of a biomarker profile.

Changing practices in the surgical management of hyperparathyroidism - a 10-year review.

AIM: Parathyroid surgery has undergone a paradigm shift over the last decade, with a move from traditional bilateral neck exploration to minimally invasive parathyroidectomy (MIP), and increasing reliance on pre- and intra-operative localization of overactive glands. We aimed to assess changing surgical practices and their impact on the management of parathyroid disease in a tertiary referral centre in the West of Ireland. METHODS: A retrospective cohort analysis of those patients undergoing a surgical intervention for parathyroid disease in the period between 1999 and 2009 in our centre was carried out. Data was analysed using PASW (v18) software. RESULTS: 248 procedures were performed, increasing from an annual rate of 6 in 1999 to 45 in 2009. 129 procedures were completed by minimally invasive means, following the introduction of MIP in 2003. Single-gland disease accounted for 87% of cases (n = 216) with carcinomas in 2 patients (0.8%). Pre-operative localization had disappointing diagnostic value, with high false negative rates for both ultrasound (37.3%) and Sestamibi Scanning (35.81%). Intra-operative adjuncts were more helpful, with intra-operative Parathyroid hormone monitoring facilitating curative resection of adenomas in 94.03% at 10 min. Median length of post-operative stay has significantly decreased from 6 days in 1999 to 1 night only in 2009 (p < 0.01, ANOVA). Those patients undergoing MIP had shorter stay than the open group (1.71 days -v-4.73, p = 0.003,t-test). CONCLUSION: The practice in our centre has shifted to a less invasive approach. Increased utilisation of intra-operative adjuncts has facilitated this change, and resulted in favourable changes in length of stay, extent of dissection, and number of patients treated.