Stephen Barnett

Correlation of Mutation Status and Survival with Predominant Histologic Subtype According to the New IASLC/ATS/ERS Lung Adenocarcinoma Classification in Stage III (N2) Patients

Introduction: We investigated the relationship between predominant subtype, according to the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society International Multidisciplinary Lung Adenocarcinoma Classification; mutation status; and patient outcome in stage III (N2) lung adenocarcinoma. Methods: We identified 69 patients with stage III (N2) lung adenocarcinoma operated on with curative intent between 1993 and 2011 who had adequate tumor tissue for molecular analysis and adequate follow-up time for survival analysis. DNA was isolated and tested for mutations using Sequenom’s OncoCarta Panel (v1.0; Sequenom, San Diego, CA). Results: The majority of tumors were acinar (26 of 69 tumors; 38%), solid (24 of 69 tumors; 35%), and micropapillary predominant (13 of 69 tumors; 19%) subtypes. EGFR and KRAS mutations were identified in 17 of 59 tumors (29%) and 13 of 59 tumors (22%), respectively. EGFR mutations occurred most often in acinar (11 of 25 tumors; 44%) and micropapillary predominant tumors (five of 13 tumors; 38%) (p = 0.009), whereas KRAS mutations occurred most often in solid predominant tumors (nine of 21 tumors; 43%) (p = 0.016). Patients with acinar predominant tumors had significantly improved overall survival compared with those with non-acinar predominant tumors (hazard ratio: 0.45; 95% confidence interval: 0.22–0.91; p = 0.026), which remained significant after adjustment for EGFR status, T-stage, sex, and age. Patients with EGFR-mutant micropapillary predominant tumors had similar survival to those with EGFR-mutant acinar predominant tumors. The predominant subtype in the primary tumor was most often seen in the N2 node in micropapillary and solid predominant tumors but not in acinar predominant tumors. Conclusions: The predominant subtype in the primary tumor was associated with overall survival in resected stage III (N2) lung adenocarcinoma and was independent of mutation status. Histologic subtyping provides important prognostic information and potentially molecular correlates.

General practice training and virtual communities of practice - a review of the literature

BackgroundGood General Practice is essential for an effective health system. Good General Practice training is essential to sustain the workforce, however training for General Practice can be hampered by a number of pressures, including professional, structural and social isolation. General Practice trainees may be under more pressure than fully registered General Practitioners, and yet isolation can lead doctors to reduce hours and move away from rural practice. Virtual communities of practice (VCoPs) in business have been shown to be effective in improving knowledge sharing, thus reducing professional and structural isolation. This literature review will critically examine the current evidence relevant to virtual communities of practice in General Practice training, identify evidence-based principles that might guide their construction and suggest further avenues for research.MethodsMajor online databases Scopus, Psychlit and Pubmed were searched for the terms “Community of Practice” (CoP) AND (Online OR Virtual OR Electronic) AND (health OR healthcare OR medicine OR “Allied Health”). Only peer-reviewed journal articles in English were selected. A total of 76 articles were identified, with 23 meeting the inclusion criteria. There were no studies on CoP or VCoP in General Practice training. The review was structured using a framework of six themes for establishing communities of practice, derived from a key study from the business literature. This framework has been used to analyse the literature to determine whether similar themes are present in the health literature and to identify evidence in support of virtual communities of practice for General Practice training.ResultsThe framework developed by Probst is mirrored in the health literature, albeit with some variations. In particular the roles of facilitator or moderator and leader whilst overlapping, are different. VCoPs are usually collaborations between stakeholders rather than single company VCoPs. Specific goals are important, but in specialised health fields sometimes less important than in business. Boundary spanning can involve the interactions of different professional groups, as well as using external experts seen in business VCoPs. There was less use of measurement in health VCoPs. Environments must be supportive as well as risk free. Additional findings were that ease of use of technology is paramount and it is desirable for VCoPs to blend online and face-to-face involvement.ConclusionsThe business themes of leadership, sponsorship, objectives and goals, boundary spanning, risk-free environment and measurements become, in the health literature, facilitation, champion and support, objectives and goals, a broad church, supportive environment, measurement benchmarking and feedback, and technology and community.General Practice training is under pressure from isolation and virtual communities of practice may be a way of overcoming isolation. The health literature supports, with some variation, the business CoP framework developed by Probst. Further research is needed to clarify whether this framework is an effective method of health VCoP development and if these VCoPs overcome isolation and thus improve rural retention of General Practice registrars.

Contemporary Results of Surgical Resection of Non-small Cell Lung Cancer After Induction Therapy: A Review of 549 Consecutive Cases

Objective: We previously reported a high mortality after induction therapy and pneumonectomy for non-small cell lung cancer. Recent reports suggest that operative mortality in these patients is declining. We analyzed our contemporary results to define operative mortality and factors determining surgical risk. Methods: Eligible patients were identified from our prospective surgical database. Complications were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events 3.0. Uni- and multivariate logistic regression models assessed the association of preoperative tests and clinical characteristics with outcome. Receiver operating characteristic curves and area under the receiver operating characteristic curve (AUC) statistics were calculated in a leave-one-out crossvalidation scheme to evaluate the predictive value of various models. Results: From January 2000 to December 2006, 549 patients underwent surgery after induction therapy. Median patient age was 64 years (range: 30–86), and 54% were women (298/549). All received chemotherapy, and 17% also had radiation. Lobectomy (388/549, 71%) and pneumonectomy (70/549, 13%) were the most common procedures. Complications occurred in 250 patients (46%), with grade 3 or higher in 23% (126/549). Inhospital mortality was 1.8% (10/549), with only one death after right pneumonectomy (1/30, 3%). Multivariate analysis showed that predicted postoperative (PPO) pulmonary function was associated with postoperative morbidity. By receiver operating characteristic curves, PPO product (AUC = 0.75, p < 0.001), PPO diffusion capacity (AUC = 0.70, p < 0.001), and preoperative % predicted PPO diffusion capacity (AUC = 0.66, p < 0.001) predicted mortality. Conclusion: Our current experience shows that resection of non-small cell lung cancer after induction therapy, including pneumonectomy, is associated with low mortality. PPO pulmonary function is the strongest predictor of operative risk and should be used to select patients for surgery.

PANCREATICODUODENECTOMY: DOES PREOPERATIVE BILIARY DRAINAGE, METHOD OF PANCREATIC RECONSTRUCTION OR AGE INFLUENCE PERIOPERATIVE OUTCOME? A RETROSPECTIVE STUDY OF 104 CONSECUTIVE CASES

Background:  Whether preoperative biliary drainage (PBD) is beneficial in reducing complications after pancreaticoduodenectomy is controversial. There remains a reluctance to consider pancreaticoduodenectomy in older patients. The major source of morbidity and potential mortality after pancreaticoduodenectomy is pancreatic fistula, which is caused by difficulties associated with the pancreatic anastomosis. The purpose of this study was to examine the effect of PBD, patient age and method of pancreatico‐enteric reconstruction on postoperative morbidity and mortality.

Implementing a virtual community of practice for family physician training: a mixed-methods case study

Background GP training in Australia can be professionally isolating, with trainees spread across large geographic areas, leading to problems with rural workforce retention. Virtual communities of practice (VCoPs) may provide a way of improving knowledge sharing and thus reducing professional isolation. Objective The goal of our study was to review the usefulness of a 7-step framework for implementing a VCoP for general practitioner (GP) training and then evaluated the usefulness of the resulting VCoP in facilitating knowledge sharing and reducing professional isolation. Methods The case was set in an Australian general practice training region involving 55 first-term trainees (GPT1s), from January to July 2012. ConnectGPR was a secure, online community site that included standard community options such as discussion forums, blogs, newsletter broadcasts, webchats, and photo sharing. A mixed-methods case study methodology was used. Results are presented and interpreted for each step of the VCoP 7-step framework and then in terms of the outcomes of knowledge sharing and overcoming isolation. Results Step 1, Facilitation: Regular, personal facilitation by a group of GP trainers with a co-ordinating facilitator was an important factor in the success of ConnectGPR. Step 2, Champion and Support: Leadership and stakeholder engagement were vital. Further benefits are possible if the site is recognized as contributing to training time. Step 3, Clear Goals: Clear goals of facilitating knowledge sharing and improving connectedness helped to keep the site discussions focused. Step 4, A Broad Church: The ConnectGPR community was too narrow, focusing only on first-term trainees (GPT1s). Ideally there should be more involvement of senior trainees, trainers, and specialists. Step 5, A Supportive Environment: Facilitators maintained community standards and encouraged participation. Step 6, Measurement Benchmarking and Feedback: Site activity was primarily driven by centrally generated newsletter feedback. Viewing comments by other participants helped users benchmark their own knowledge, particularly around applying guidelines. Step 7, Technology and Community: All the community tools were useful, but chat was limited and users suggested webinars in future. A larger user base and more training may also be helpful. Time is a common barrier. Trust can be built online, which may have benefit for trainees that cannot attend face-to-face workshops. Knowledge sharing and isolation outcomes: 28/34 (82%) of the eligible GPT1s enrolled on ConnectGPR. Trainees shared knowledge through online chat, forums, and shared photos. In terms of knowledge needs, GPT1s rated their need for cardiovascular knowledge more highly than supervisors. Isolation was a common theme among interview respondents, and ConnectGPR users felt more supported in their general practice (13/14, 92.9%). Conclusions The 7-step framework for implementation of an online community was useful. Overcoming isolation and improving connectedness through an online knowledge sharing community shows promise in GP training. Time and technology are barriers that may be overcome by training, technology, and valuable content. In a VCoP, trust can be built online. This has implications for course delivery, particularly in regional areas. VCoPs may also have a specific role assisting overseas trained doctors to interpret their medical knowledge in a new context.

The Role of Cancer-Testis Antigens as Predictive and Prognostic Markers in Non-Small Cell Lung Cancer

Background Cancer-Testis Antigens (CTAs) are immunogenic proteins that are poor prognostic markers in non-small cell lung cancer (NSCLC). We investigated expression of CTAs in NSCLC and their association with response to chemotherapy, genetic mutations and survival. Methods We studied 199 patients with pathological N2 NSCLC treated with neoadjuvant chemotherapy (NAC; n = 94), post-operative observation (n = 49), adjuvant chemotherapy (n = 47) or unknown (n = 9). Immunohistochemistry for NY-ESO-1, MAGE-A and MAGE-C1 was performed. Clinicopathological features, response to neoadjuvant treatment and overall survival were correlated. DNA mutations were characterized using the Sequenom Oncocarta panel v1.0. Affymetrix data from the JBR.10 adjuvant chemotherapy study were obtained from a public repository, normalised and mapped for CTAs. Results NY-ESO-1 was expressed in 50/199 (25%) samples. Expression of NY-ESO-1 in the NAC cohort was associated with significantly increased response rates (P = 0.03), but not overall survival. In the post-operative cohort, multivariate analyses identified NY-ESO-1 as an independent poor prognostic marker for those not treated with chemotherapy (HR 2.61, 95% CI 1.28–5.33; P = 0.008), whereas treatment with chemotherapy and expression of NY-ESO-1 was an independent predictor of improved survival (HR 0.267, 95% CI 0.07–0.980; P = 0.046). Similar findings for MAGE-A were seen, but did not meet statistical significance. Independent gene expression data from the JBR.10 dataset support these findings but were underpowered to demonstrate significant differences. There was no association between oncogenic mutations and CTA expression. Conclusions NY-ESO-1 was predictive of increased response to neoadjuvant chemotherapy and benefit from adjuvant chemotherapy. Further studies investigating the relationship between these findings and immune mechanisms are warranted.

Perceptions of family physician trainees and trainers regarding the usefulness of a virtual community of practice

Background Training for Australian general practice, or family medicine, can be isolating, with registrars (residents or trainees) moving between rural and urban environments, and between hospital and community clinic posts. Virtual communities of practice (VCoPs), groups of people sharing knowledge about their domain of practice online and face-to-face, may have a role in overcoming the isolation associated with general practice training. Objective This study explored whether Australian general practice registrars and their supervisors (trainers) would be able to use, and would be interested in using, a VCoP in the form of a private online network for work and training purposes. It also sought to understand the facilitators and barriers to intention to use such a community, and considers whether any of these factors may be modifiable. Methods A survey was developed assessing computer, Internet, and social media access and usage, confidence, perceived usefulness, and barriers, facilitators, and intentions to use a private online network for training purposes. The survey was sent by email link to all 139 registrars and 224 supervisors in one of Australia’s 17 general practice training regions. Complete and usable responses were received from 131 participants (response rate=0.4). Results Most respondents had access to broadband at home (125/131, 95.4%) and at work (130/131, 99.2%). Registrars were more likely to spend more than 2 hours on the Internet (P=.03), and to use social media sites for nonwork purposes (P=.01). On a 5-point Likert scale, confidence was high (mean 3.93, SD 0.63) and was negatively associated with higher age (P=.04), but not associated with training stage. Social media confidence was lower, with registrars more confident than supervisors for almost all social media activities. On a 5-point Likert scale, overall usefulness was scored positively (n=123, mean 3.63, SD 0.74), and was not significantly associated with age or training level. The main concerns of respondents were worries about privacy (registrar: 61/81, 75.3%; supervisor: 30/50, 60.0%) and insufficient time (registrar: 41/81, 50.6%; supervisor: 36/50, 72.0%). Using a multivariate generalized linear regression model, training stage and perceived usefulness were positively predictive, and concerns about privacy and time were negatively predictive of intention to use a private online network. Conclusions General practice registrars and supervisors are interested in using a private online network, or VCoP, for work and training purposes. Important considerations are the extent to which concerns such as privacy and usefulness may be overcome by training and support to offset some other concerns, such as time barriers. Participants at an early stage in their training are more receptive to using an online network. More senior registrars and supervisors may benefit from more training and promotion of the online network to improve their receptiveness.

Usefulness of a virtual community of practice and Web 2.0 tools for general practice training: experiences and expectations of general practitioner registrars and supervisors

General practice training is a community of practice in which novices and experts share knowledge. However, there are barriers to knowledge sharing for general practioner (GP) registrars, including geographic and workplace isolation. Virtual communities of practice (VCoP) can be effective in overcoming these barriers using social media tools. The present study examined the perceived usefulness, features and barriers to implementing a VCoP for GP training. Following a survey study of GP registrars and supervisors on VCoP feasibility, a qualitative telephone interview study was undertaken within a regional training provider. Participants with the highest Internet usage in the survey study were selected. Two researchers worked independently conducting thematic analysis using manual coding of transcriptions, later discussing themes until agreement was reached. Seven GP registrars and three GP supervisors participated in the study (average age 38.2 years). Themes emerged regarding professional isolation, potential of social media tools to provide peer support and improve knowledge sharing, and barriers to usage, including time, access and skills. Frequent Internet-using GP registrars and supervisors perceive a VCoP for GP training as a useful tool to overcome professional isolation through improved knowledge sharing. Given that professional isolation can lead to decreased rural work and reduced hours, a successful VCoP may have a positive outcome on the rural medical workforce.

The Immune Microenvironment, Genome-wide Copy Number Aberrations, and Survival in Mesothelioma

Introduction: Results of recent clinical studies of immune checkpoint inhibitors in malignant pleural mesothelioma (MPM) have dampened initial enthusiasm. However, the immune environment and targets of these treatments such as programmed cell death protein 1 and its ligand programmed death ligand 1 (PD‐L1) have not been well characterized in MPM. Using a large cohort of patients, we investigated PD‐L1 expression, immune infiltrates, and genome‐wide copy number status and correlated them to clinicopathological features. Methods: Tissue microarrays were constructed and stained with PD‐L1(clone E1L3N [Cell Signaling Technology, Danvers, MA]), cluster of differentiation 4, cluster of differentiation 8, and forkhead box P3 antibodies. PD‐L1 positivity was defined as at least 5% membranous staining regardless of intensity, and high PD‐L1 positivity was defined as at least 50%. Genomic DNA from a representative subset of 113 patients was used for genome‐wide copy number analysis. The percent genome alteration was computed as a proxy for genomic instability, and statistical analyses were used to relate copy number aberrations to other variables. Results: Among 329 patients evaluated, PD‐L1 positivity was detected in 130 of 311 (41.7%), but high PD‐L1 positivity was seen in only 30 of 311 (9.6%). PD‐L1 positivity correlated with nonepithelioid histological subtype and increased infiltration with cluster of differentiation 4–positive, cluster of differentiation 8–positive, and forkhead box P3–positive lymphocytes. High PD‐L1–positive expression correlated with worse prognosis (hazard ratio = 2.37, 95% confidence interval: 1.57–3.56, p < 0.001) in univariate analysis but not in multivariate analysis. Higher percent genome alteration was associated with epithelioid histological subtype and poorer survival (hazard ratio = 1.59, 95% confidence interval: 1.01–2.5, p = 0.04) but not PD‐L1 expression. Conclusions: PD‐L1 expression was associated with nonepithelioid MPM, poor clinical outcome, and increased immunological infiltrates. Increased genomic instability did not correlate with PD‐L1 expression but was associated with poorer survival.

Respiratory-gated (4D) FDG-PET detects tumour and normal lung response after stereotactic radiotherapy for pulmonary metastases.

Abstract Background. Response assessment after stereotactic ablative body radiotherapy (SABR) in lung can be confounded by radiation-induced inflammation, fibrosis and subsequent alteration of tumour motion. The purpose of this prospective pilot study was to evaluate the utility of four-dimensional (4D) FDG-PET/CT for post-SABR tumour and normal lung response assessment in pulmonary oligometastases. Material and methods. Patients enrolled from February 2010 to December 2011 in this prospective ethics approved study had 1–2 pulmonary metastases on staging FDG-PET. Serial contemporaneous 3D and 4D FDG-PET/CT scans were performed at baseline, 14 days and 70 days after a single fraction of 26 Gy SABR. Tumour response was evaluated in 3D and 4D using SUVmax, RECIST and PERCIST criteria. Normal lung radiotoxicity was evaluated using SUVmean within 0–2 Gy, 2–5 Gy, 5–10 Gy, 10–20 Gy and 20 + Gy isodose volumes. Results. In total, 17 patients were enrolled of which seven were ineligible due to interval progression from staging PET to baseline 4D-PET. The mean time between scans was 62 days. At a median follow-up of 16 months, 10 patients with 13 metastases received SABR, with no patient having local progression. The vector of tumour motion was larger in patients with discordant 3D and 4D PET PERCIST response (p < 0.01), with a mean (± SEM) motion of 10.5 mm (± 0.96 mm) versus 6.14 mm (± 0.81 mm) in those patients with concordant 3D and 4D response. Surrounding normal lung FDG uptake at 70 days was strongly correlated to delivered radiation dose (r2 = 0.99, p < 0.01), with significant elevations across all dose levels (p ≤ 0.05), except the < 2 Gy volume (p = 0.30). Conclusions. We demonstrate high rates of interval progression between staging PET scans in patients with oligometastases. We found that tumour response on conventional 3D PET is not concordant with 4D PET for tumours with large motion. Normal lung metabolic uptake is strongly dose dependent after SABR, a novel finding that should be further validated.