Refining pathological evaluation of neoadjuvant therapy for adenocarcinoma of the esophagus

AIM: To assess tumour regression grade (TRG) and lymph node downstaging to help define patients who benefit from neoadjuvant chemotherapy.METHODS: Two hundred and eighteen consecutive patients with adenocarcinoma of the esophagus or gastro-esophageal junction treated with surgery alone or neoadjuvant chemotherapy and surgery between 2005 and 2011 at a single institution were reviewed. Triplet neoadjuvant chemotherapy consisting of platinum, fluoropyrimidine and anthracycline was considered for operable patients (World Health Organization performance status ? 2) with clinical stage T2-4 N0-1. Response to neoadjuvant chemotherapy (NAC) was assessed using TRG, as described by Mandard et al. In addition lymph node downstaging was also assessed. Lymph node downstaging was defined by cN1 at diagnosis: assessed radiologically (computed tomography, positron emission tomography, endoscopic ultrasonography), then pathologically recorded as N0 after surgery; ypN0 if NAC given prior to surgery, or pN0 if surgery alone. Patients were followed up for 5 years post surgery. Recurrence was defined radiologically, with or without pathological confirmation. An association was examined between t TRG and lymph node downstaging with disease free survival (DFS) and a comprehensive range of clinicopathological characteristics.RESULTS: Two hundred and eighteen patients underwent esophageal resection during the study interval with a mean follow up of 3 years (median follow up: 2.552, 95%CI: 2.022-3.081). There was a 1.8% (n = 4) inpatient mortality rate. One hundred and thirty-six (62.4%) patients received NAC, with 74.3% (n = 101) of patients demonstrating some signs of pathological tumour regression (TRG 1-4) and 5.9% (n = 8) having a complete pathological response. Forty four point one percent (n = 60) had downstaging of their nodal disease (cN1 to ypN0), compared to only 15.9% (n = 13) that underwent surgery alone (pre-operatively overstaged: cN1 to pN0), (P < 0.0001). Response to NAC was associated with significantly increased DFS (mean DFS; TRG 1-2: 5.1 years, 95%CI: 4.6-5.6 vs TRG 3-5: 2.8 years, 95%CI: 2.2-3.3, P < 0.0001). Nodal down-staging conferred a significant DFS advantage for those patients with a poor primary tumour response to NAC (median DFS; TRG 3-5 and nodal down-staging: 5.533 years, 95%CI: 3.558-7.531 vs TRG 3-5 and no nodal down-staging: 1.114 years, 95%CI: 0.961-1.267, P < 0.0001).CONCLUSION: Response to NAC in the primary tumour and in the lymph nodes are both independently associated with improved DFS

Understanding assurance in the Australian self-managed superannuation fund industry

Abstract Using proprietary data, this study examines auditor industry specialisation, professional brand effects and non-audit services (NAS) in the self-managed superannuation fund (SMSF) sector, the fastest growing and largest segment of the Australian $1.75 trillion retirement savings industry. We consider the impact of industry leadership for a large sample of SMSF audits for the three years to June 2010. After controlling for factors known to determine audit fees, we find evidence of fee discounting for the leading suppliers of SMSF audits, consistent with Simunic (1980)’s assertion of competition in the small audit client market. When considering the impact of professional affiliations, we find that registered company auditors and members of professional bodies who comply with auditing and ethical standards receive a fee premium. In terms of auditor independence, the supply of NAS is shown to improve the auditors’ ability to report breaches, suggesting no independence concerns arising from joint supply of audit and NAS in this setting

Economic and Practical Factors in Diagnosing HNPCC Using Clinical Criteria, Immunohistochemistry and Microsatellite Instability Analysis

Aim: To determine a cost-efficient strategy for HNPCC molecular diagnostic testing. Methods: 138 families referred to a Regional Genetics Service had hMLH1 and hMSH2 mutation analysis. The sensitivity and specificity of clinical selection criteria with or without immunohistochemistry (IHC) and microsatellite instability (MSI) analysis to further refine case selection and the effect of these approaches on the cost of mutation analysis were examined. Results: Clearly deleterious mutations were identified in 49/138 (35.5%) of all families tested. The most sensitive criteria for identifying families with MMR mutations were the full Bethesda guidelines but these have poor specificity. IHC and MSI were useful pre-screening tools. Conclusion: A cost-efficient approach in laboratories where IHC and/or MSI analysis are available, is to use inclusive (non-specific) criteria to select cases, followed by IHC and then MSI. Where one or both results are abnormal, proceed to further mutation analysis. Where MSI or IHC or tumour blocks are not available, more restrictive clinical criteria may be more appropriate for cost-efficient case selection

Double Pass Gain in Helium-Xenon Discharges in Hollow Optical Fibres at 3.5 μm

With recent advances in low-loss hollow core optical fibre technology [1], the concept of a flexible electrically pumped gas discharge laser has become a reality. Such a device would be capable of having a very narrow discharge tube, which has been shown to increase gain and output power in neutral noble gas lasers, while eliminating the need for long, rigorously straight glass tubes, a problem that has plagued past attempts to exploit this behaviour [2]. The narrow bore tubes have however made the discharge parameters harder to achieve, but recent work with DC-excited glow discharges provided the first indications of gain on the 3.11 μm, 3.37 μm and 3.51 μm Xenon transmission lines in fibres of over 1 m in length [3]. Here we continue with that work by carrying out a double pass experiment with these discharges, as a step towards a full laser cavity

Is a reduction in the individual vigilance of mothers a key evolutionary driver of group formation in white rhinos?

A key benefit and evolutionary driver of group living is reduced predation risk. In white rhinos, groups comprise adult females, their calves and one to six unrelated subadults. Subadults benefit from group living through exposure to novel areas, and protection from territorial males (i.e. ‘buddy system’). In contrast, it is unclear whether mothers benefit from group living. To determine if they benefit, or if there is simply no cost, we recorded the vigilance of white rhino mothers in different-sized groups. We predicted that as group size increased, calves would have lower predation risk and mothers would reduce their vigilance. In contrast, we found that vigilance did not decrease as group size increased. Our findings thus indicate that decreased vigilance is not a benefit that white rhino mothers gain from living in groups. Also, costs of group formation are minimal for mothers as their large body size and ability to feed on a wide range of grasses reduces competition with other group members. As a result, we suggest that the benefits obtained by subadults, coupled with the lack of costs to adult females, are the main drivers of group formation in white rhinos.We thank Ezemvelo KZN Wildlife and the staff of the Hluhluwe-iMfolozi Park for permission to undertake the study. We acknowledge funds made available by the University of Pretoria (P.W.B), and the National Research Foundation (NRF) (A.M.S.). Any opinion, findings and conclusions or recommendations expressed are those of the authors and therefore the NRF does not accept any liability in regard thereto. The experimental procedure was purely observational and noninvasive, and consistent with the University of Pretoria and South African animal ethic protocols. Finally, we thank Graham Kerley and an anonymous reviewer for their valuable comments.http://africanzoology.journals.ac.za/am2013ab201

Tumour infiltrating lymphocytes correlate with improved survival in patients with oesophageal adenocarcinoma

BACKGROUND: Oesophageal adenocarcinoma (OAC) is increasingly common in the west, and survival remains poor at 10-15 % at 5 years. Immune responses are increasingly implicated as a determining factor of tumour progression. The ability of lymphocytes to recognise tumour antigens provides a mechanism for a host immune attack against cancer providing a potential treatment strategy.MATERIALS AND METHODS: Tumour infiltrating lymphocytes (TILs: CD3+, CD4+, CD8+ and FOXp3+) were assessed by immunohistochemistry using tissue microarrays in a contemporary and homogeneous cohort of OAC patients (n = 128) undergoing curative treatment.RESULTS: Multivariate analysis identified three independent prognostic factors for improved cancer-specific survival (CSS): increased CD8+ TILs (p = 0.003), completeness of resection (p < 0.0001) and lower pathological N stage (p < 0.0001). Independent prognostic factors for favourable disease-free survival included surgery-only treatment (p = 0.015), completeness of resection (p = 0.001), increased CD8+ TILs (p < 0.0001) and reduced pathological N stage (p < 0.0001). Higher levels of TILs in the pathological specimen were associated with significant pathological response to neoadjuvant chemotherapy (NAC). On multivariate analysis increased levels of CD4+ (p = 0.017) and CD8+ TILs (p = 0.005) were associated with significant local tumour regression and lymph node downstaging, respectively.DISCUSSION: Our results establish an association of TILs and survival in OAC, as seen in other solid tumours, and identify particular TIL subsets that are present at higher levels in patients who responded to NAC compared to non-responders. These findings highlight potential therapeutic strategies in EAC based on utilising the host immunological response and highlight the immune responses biomarker potential