Evidence for the antagonistic form of CXC-motif chemokine CXCL10 in serous epithelial ovarian tumours.

Patients with high-grade, serous epithelial ovarian carcinoma (HGSOC) are generally diagnosed with extensive peritoneal metastases, and exhibit 5-year survival rates <30%. A subset of these tumours, defined as "immunoreactive," overexpress mRNA encoding the T-cell-recruiting chemokine CXCL10 (10-kDa interferon gamma-induced protein; C-X-C motif chemokine 10). Tumour-infiltrating CD4(+) CD8(+) T-cells are a well-documented, positive prognostic indicator for HGSOC patients; paradoxically, however, patients diagnosed with HGSOC (overexpressing CXCL10 and therefore theorised to recruit T-cells) typically exhibit poor survival. Recently, an "antagonistic" CXCL10 variant was identified that inhibited leucocyte recruitment to inflamed liver in vivo (Casrouge et al., J Clin Invest 2011;121:308-17). We hypothesised that "immunoreactive" HGSOC might also express antagonistic CXCL10, interfering with leucocyte recruitment and contributing to poor patient prognosis. CXCL10 expression was analysed in HGSOC tissues grouped according to pathology, grade and FIGO stage at diagnosis, and its localisation and association with T-cells established by immunohistochemical staining in tissue microarrays. CXCL10 expression was increased in a subset of serous epithelial tumour samples; however, it did not correlate well with CD45-positive tumour infiltrate. Immunoprecipitation and de novo sequence analysis of CXCL10 identified the N-terminally cleaved, "antagonistic" variant of CXCL10 specifically in malignant tumours, and not in benign ovarian disease. The data demonstrate the presence of the antagonistic form of CXCL10 in HGSOC for the first time, and provide a partial explanation for reduced leucocyte infiltration observed in these tumours. We suggest that CXCL10 cleavage and subsequent antagonism of immune cell recruitment may be a feature of the "immunoreactive" HGSOC subtype, leading to early impairment of the immune response and subsequently worsening patient prognosis.

Effect of using a safety checklist on patient complications after surgery: a systematic review and meta-analysis.

BACKGROUND: Previous before-and-after studies indicate that the use of safety checklists in surgery reduces complication rates in patients. METHODS: A systematic review of studies was undertaken using MEDLINE, CINAHL, Proquest, and the Cochrane Library to identify studies that evaluated the effects of checklist use in surgery on complication rates. Study quality was assessed using the Methodological Index for Nonrandomized Studies. The pooled risk ratio (RR) was estimated using both fixed and random effects models. For each outcome, the number needed to treat (NNT) and the absolute risk reduction (ARR) were also computed. RESULTS: Of the 207 intervention studies identified, 7 representing 37,339 patients were included in meta-analyses, and all were cohort studies. Results indicated that the use of checklists in surgery compared with standard practice led to a reduction in any complication (RR, 0.63; 95% CI, 0.58 to 0.72; P < 0.0001; ARR, 3.7%; NNT, 27) and wound infection (RR, 0.54; 95% CI, 0.40 to 0.72; P = 0.0001; ARR, 2.9%; NNT, 34) and also reduction in blood loss (RR, 0.56; 95% CI, 0.45 to 0.70; P = 0.0001; ARR, 3.8%; NNT, 33). There were no significant reductions in mortality (RR, 0.79; 95% CI, 0.57 to 1.11; P = 0.191; ARR, 0.44%; NNT, 229), pneumonia (RR, 1.03; 95% CI, 0.73 to 1.4; P = 0.857; ARR, 0.04%; NNT, 2,512), or unplanned return to operating room (RR, 0.75; 95% CI, 0.56 to 1.02; P = 0.068; ARR, 0.52%; NNT, 192). CONCLUSION: Notwithstanding the lack of randomized controlled trials, synthesis of the existing body of evidence suggests a relationship between checklist use in surgery and fewer postoperative complications.

The utility of isotope-coded protein labeling for prioritization of proteins found in ovarian cancer patient urine.

Urine offers a number of attractive features as a sample type for biomarker discovery, including noninvasive sampling, quantity and availability, stability, and a narrow dynamic range. In this study we report the first application of isotope coded protein labeling (ICPL), coupled with in-solution isoelectric fractionation and LC-MALDI-TOF/TOF, to examine and prioritize urinary proteins from ovarian cancer patients. Following the definition of stringent exclusion criteria a total of 579 proteins were identified with 43% providing quantitation data. Protein abundance changes were validated for selected proteins by ESI-Qq-TOF MS, following which Western blot and immunohistochemical analysis by tissue microarray was used to explore the biological relevance of the proteins identified. Several established markers (e.g., HE4, osteopontin) were identified at increased levels in ovarian cancer patient urine, validating the approach used; we also identified a number of potential marker candidates (e.g., phosphatidylethanolamine binding protein 1, cell-adhesion molecule 1) previously unreported in the context of ovarian cancer. We conclude that the ICPL strategy for identification and relative quantitation of urine proteins is an appropriate tool for biomarker discovery studies, and can be applied for the selection of potential biomarker candidates for further characterization.

Team communications in surgery - creating a culture of safety.

As a key department within a healthcare organisation, the operating room is a hazardous environment, where the consequences of errors are high, despite the relatively low rates of occurrence. Team performance in surgery is increasingly being considered crucial for a culture of safety. The aim of this study was to describe team communication and the ways it fostered or threatened safety culture in surgery. Ethnography was used, and involved a 6-month fieldwork period of observation and 19 interviews with 24 informants from nursing, anaesthesia and surgery. Data were collected during 2009 in the operating rooms of a tertiary care facility in Queensland, Australia. Through analysis of the textual data, three themes that exemplified teamwork culture in surgery were generated: "building shared understandings through open communication"; "managing contextual stressors in a hierarchical environment" and "intermittent membership influences team performance". In creating a safety culture in a healthcare organisation, a team's optimal performance relies on the open discussion of teamwork and team expectation, and significantly depends on how the organisational culture promotes such discussions.

Effects of a Brief Team Training Program on Surgical Teams' Nontechnical Skills: An Interrupted Time-Series Study.

BACKGROUND: Up to 60% of adverse events in surgery are the result of poor communication and teamwork. Nontechnical skills in surgery (NOTSS) are critical to the success of surgery and patient safety. The study aim was to evaluate the effect of a brief team training intervention on teams' observed NOTSS. METHODS: Pretest-posttest interrupted time-series design with statistical process control analysis was used to detect longitudinal changes in teams' NOTSS. We evaluated NOTSS using the revised NOTECHS weekly for 20 to 25 weeks before and after implementation of a team training program. RESULTS: We observed 179 surgical procedures with cardiac, vascular, upper gastrointestinal, and hepatobiliary teams. Mean posttest NOTECHS scores increased across teams, showing special cause variation. There were also significant before and after improvements in NOTECHS scores in respect to professional role and in the use of the Surgical Safety Checklist. CONCLUSIONS: Our results suggest associated improvements in teams' NOTSS after implementation of the team training program.

Keratin-14 (KRT14) Positive Leader Cells Mediate Mesothelial Clearance and Invasion by Ovarian Cancer Cells.

Epithelial ovarian cancer metastasis is driven by spheroids, which are heterogeneous cancer cell aggregates released from the primary tumour mass that passively disseminate throughout the peritoneal cavity to promote tumour spread, disease recurrence, and acquired chemoresistance. Despite their clinical importance, the molecular events that control spheroid attachment and invasion into underlying healthy tissues remain poorly understood. We examined a novel in vitro invasion model using imaging mass spectrometry to establish a "snapshot" of the spheroid/mesothelial interface. Amongst numerous adhesion-related proteins, we identified a sub-population of highly motile, invasive cells that expressed the basal epithelial marker KRT14 as an absolute determinant of invasive potential. The loss of KRT14 completely abrogated the invasive capacity, but had no impact on cell viability or proliferation, suggesting an invasion-specific role. Our data demonstrate KRT14 cells as an ovarian cancer "leader cell" phenotype underlying tumor invasion, and suggest their importance as a clinically relevant target in directed anti-tumour therapies.

The molecular origin and taxonomy of mucinous ovarian carcinoma.

Mucinous ovarian carcinoma (MOC) is a unique subtype of ovarian cancer with an uncertain etiology, including whether it genuinely arises at the ovary or is metastatic disease from other organs. In addition, the molecular drivers of invasive progression, high-grade and metastatic disease are poorly defined. We perform genetic analysis of MOC across all histological grades, including benign and borderline mucinous ovarian tumors, and compare these to tumors from other potential extra-ovarian sites of origin. Here we show that MOC is distinct from tumors from other sites and supports a progressive model of evolution from borderline precursors to high-grade invasive MOC. Key drivers of progression identified are TP53 mutation and copy number aberrations, including a notable amplicon on 9p13. High copy number aberration burden is associated with worse prognosis in MOC. Our data conclusively demonstrate that MOC arise from benign and borderline precursors at the ovary and are not extra-ovarian metastases.

Changes in surgical team performance and safety climate attitudes following expansion of perioperative services: a repeated-measures study.

Objective The aim of the present study was to describe process changes in surgical team performance and team members' attitudes to safety culture following hospital relocation and expansion of perioperative services. Methods The study was a naturalistic study using structured observations and surveys to assess non-technical skills (NTS; i.e. communication, teamwork, situational awareness, decision making and leadership) in surgery. This interrupted time series design used mixed-linear regression models to examine the effect of phase (before and after hospital relocation) on surgical teams' NTS and their processes that may affect performance. Differences in self-reported teamwork and safety climate attitudes were also examined. Results In all, 186 procedures (100 before and 81 after hospital relocation) were observed across teams working in general, paediatric, orthopaedic and thoracic surgeries. Interobserver agreement ranged from 86% to 95%. An effect of phase was found, indicating that there were significant improvements after relocation in the use of NTS by the teams observed (P=0.020; 95% confidence interval 1.9-4.7). Conclusions The improvements seen in surgical teams' NTS performance and safety culture attitudes may be related to the move to a new state-of-the-art perioperative department. What is known about the topic? Patient safety in surgery relies on optimal team performance, underpinned by effective NTS. What does this paper add? The NTS of surgical teams may be improved through ergonomic innovations that promote teams' shared mental models. What are the implications for practitioners? Effective multidisciplinary teamwork relies on a combination of NTS and ergonomic factors, which inherently contribute to team performance and safety climate attitudes.

Discovery and Validation of Novel Protein Biomarkers in Ovarian Cancer Patient Urine.

PURPOSE: For the vast majority of ovarian cancer patients, optimal surgical debulking remains a key prognostic factor associated with improved survival. A standardized, biomarker-based test, to preoperatively discriminate benign from malignant disease and inform appropriate patient triage, is highly desirable. However, no fit-for-purpose biomarkers have yet been identified. EXPERIMENTAL DESIGN: We conducted a pilot study consisting of 40 patient urine samples (20 from each group), using label-free quantitative (LFQ) mass spectrometry, to identify potential biomarker candidates in urine from individual ovarian cancer patients. To validate these changes, we used parallel reaction monitoring (PRM) to investigate their abundance in an independent validation cohort (n = 20) of patient urine samples. RESULTS: LFQ analyses identified 4394 proteins (17 027 peptides) in a discovery set of 20 urine samples. Twenty-three proteins were significantly elevated in the malignant patient group compared to patients with benign disease. Several proteins, including LYPD1, LYVE1, PTMA, and SCGB1A1 were confirmed to be enriched in the urine of ovarian cancer patients using PRM. We also identified the established ovarian cancer biomarkers WFDC2 (HE4) and mesothelin (MSLN), validating our approach. CONCLUSIONS AND CLINICAL RELEVANCE: This is the first application of a LFQ-PRM workflow to identify and validate ovarian cancer-specific biomarkers in patient urine samples.

Evaluation of a Brief Team Training Intervention in Surgery: A Mixed-Methods Study.

The aim of this study was to evaluate a brief team training program in relation to teams' observed nontechnical skills (NTSs) in surgery, teams' perceptions of safety culture, and the training implementation. We used mixed methods to analyze structured observations of 179 surgeries, semistructured interviews with surgical team members from four selected surgical specialties, and a survey. There were significant (P < .001) improvements in surgical teams' observed NTSs and in the use of the World Health Organization's Surgical Safety Checklist after participation in the training program. Nonsignificant results included increased perceived safety climate and decreased perceived teamwork climate. From participant interviews, we identified that production pressure and time constraints were the biggest barriers to implementation and the greatest enabler was the organization's support for staff education initiatives. Most participants perceived the content of the program to be useful. These results highlight the complexities inherent in the development and evaluation of interdisciplinary patient safety interventions.

Correlates of non-technical skills in surgery: a prospective study.

BACKGROUND: Communication and teamwork failures have frequently been identified as the root cause of adverse events and complications in surgery. Few studies have examined contextual factors that influence teams' non-technical skills (NTS) in surgery. The purpose of this prospective study was to identify and describe correlates of NTS. METHODS: We assessed NTS of teams and professional role at 2 hospitals using the revised 23-item Non-TECHnical Skills (NOTECHS) and its subscales (communication, situational awareness, team skills, leadership and decision-making). Over 6 months, 2 trained observers evaluated teams' NTS using a structured form. Interobserver agreement across hospitals ranged from 86% to 95%. Multiple regression models were developed to describe associations between operative time, team membership, miscommunications, interruptions, and total NOTECHS and subscale scores. RESULTS: We observed 161 surgical procedures across 8 teams. The total amount of explained variance in NOTECHS and its 5 subscales ranged from 14% (adjusted R2 0.12, p<0.001) to 24% (adjusted R2 0.22, p<0.001). In all models, inverse relationships between the total number of miscommunications and total number of interruptions and teams' NTS were observed. CONCLUSIONS: Miscommunications and interruptions impact on team NTS performance.

Building shared situational awareness in surgery through distributed dialog.

BACKGROUND: Failure to convey time-critical information to team members during surgery diminishes members' perception of the dynamic information relevant to their task, and compromises shared situational awareness. This research reports the dialog around clinical decisions made by team members in the time-pressured and high-risk context of surgery, and the impact of these communications on shared situational awareness. METHODS: Fieldwork methods were used to capture the dynamic integration of individual and situational elements in surgery that provided the backdrop for clinical decisions. Nineteen semistructured interviews were performed with 24 participants from anesthesia, surgery, and nursing in the operating rooms of a large metropolitan hospital in Queensland, Australia. Thematic analysis was used. RESULTS: The domain "coordinating decisions in surgery" was generated from textual data. Within this domain, three themes illustrated the dialog of clinical decisions, ie, synchronizing and strategizing actions, sharing local knowledge, and planning contingency decisions based on priority. CONCLUSION: Strategies used to convey decisions that enhanced shared situational awareness included the use of "self-talk", closed-loop communications, and "overhearing" conversations that occurred at the operating table. Behaviors that compromised a team's shared situational awareness included tunneling and fixating on one aspect of the situation.

Factors that influence the expected length of operation: results of a prospective study.

BACKGROUND: In the operating room, factors such as interruptions, communication failures, team familiarity and the unpredictability of unplanned cases can prolong the length of an operation, and lead to inefficiency and increased costs. However, little is known about the extent to which such factors contribute to extending the expected length of an operation. Aim To describe factors that prolong the expected length of an operation. METHODS: Structured observations were performed on a purposive sample of 160 surgical procedures across 10 specialties of planned and unplanned surgeries. During the 6-month period, a trained observer structured observations. Bivariate correlations and a standard multiple regression model were developed to describe associations among unplanned operations, interruptions, prebriefings, team familiarity, communication failures and the outcome, and deviation from expected operation time. RESULTS: Of the three explanatory variables entered into the regression model, the only significant predictor of deviation in expected length of operation was the number of communication failures (p=0.013). This model explained 4.5% of the variance in deviation in expected length of operation (p=0.018). CONCLUSIONS: The results of this study validate the role of prospective observational research methods in unveiling critical factors that contribute to deviation in expected length of operation. These results have the potential to inform evidence-based interventions aimed at ameliorating the effects of miscommunications, hence improve patient safety.

Interruptions and miscommunications in surgery: an observational study.

In surgery, as much as 30% of procedure-specific information may be lost as a result of miscommunication. We assessed the relationship between interruptions, team familiarity, and miscommunications across a purposive sample of 160 surgical procedures in 10 specialties during a six-month period. Descriptive analysis was used to quantify interruptions in respect to the source (ie, conversational, procedural) and type of miscommunication (ie, audience, purpose, occasion, content, experience). Results revealed an inverse correlation between the length of time that teams had worked together and the number of miscommunications in surgery (τ = -.33, P < .01). There was a positive correlation between the number of intraoperative interruptions and the number of miscommunications (τ = .30, P < .01). These results may help to inform the development of evidence-based interventions designed to mitigate the effects of miscommunications in surgery.