Search

Schools and school teachers often focus on content aimed at delaying sexual debut and preventing teenage pregnancy, and address the impacts of risky behaviours on infant health. Infant simulators are increasingly used in health education courses. However, it is unclear how effective this education is. In this review, we examined the evidence for the effectiveness and use of pregnancy/parenting education programmes for school-aged students using infant simulators. Infant simulators are lifelike replicas of human newborn babies that have electronic capacity to mimic a range of infant behaviours. These may include feeding, comfort needs and nappy changing. Responses to these replicated behaviours may be recorded to provide feedback of the adequacy of the response for educational purposes and provide feedback to prospective parents and caregivers. This review followed the guidelines for conducting a scoping review developed by Joanna Briggs Institute (JBI). After following the process as recommended by the JBI, 32 eligible articles were selected for inclusion. Eight themes emerged from the analysis and it was found that the use of infant simulators in terms of effectiveness was not conclusive. This may be due to lack of longitudinal studies examining the impact of the education provided. Furthermore, the literature did not address innovations of infant simulators that replicate infants with particular characteristics, those with fetal alcohol spectrum disorder, shaken baby syndrome or challenges from parental substance use. Further research is required to determine the long-term impact of using infant simulators on reducing risky behaviours. Given these challenges, it is important to support initiatives for sex, pregnancy and parenting education among all students., (© The Author(s) 2024. Published by Oxford University Press.)

Background and Objective: The tumor microenvironment (TME) in non-muscle-invasive bladder cancer (NMIBC) plays an important role in the anticancer response. We aimed to identify the prognostic biomarkers in the TME of patients with NMIBC for progression to ≥T2., Methods: From our institutional database, 40 patients with T1 high-risk NMIBC who progressed were pair matched for Club Urologico Español de Tratamiento Oncologico (CUETO) progression variables with 80 patients who never progressed despite longer follow-up. Progression was defined as ≥T2 or extravesical disease. Patients were treated at least with bacillus Calmette-Guérin (BCG) induction (five or more of six doses). Immunohistochemical (IHC) markers for the TME were used on tissue at first T1 diagnosis: CD8-PanCK, GZMB-CD8-FOXP3, CD163, PD-L1 SP142/SP263, fibroblast activation protein-α (FAP), and CK5-GATA3. Full tissue slides were annotated digitally. Relative marker area (IHC-positive area/total area) or density (IHC-positive cells per area; n /mm 2 ) was calculated, differentiating between regions of interest (ROIs; T1, Ta, and carcinoma in situ) and between compartments (stromal, epithelial, and combined). Differences in IHC variables were assessed using the t test, for continuous variables using analysis of variance and comparisons of more than two groups using Tukey's test. Conditional logistic regression for progression at 5-yr follow-up was performed with clusters based on pair matching., Key Findings and Limitations: Only FAP expression (increase per 50%) in T1 (odds ratio [OR]: 1.33; 95% confidence interval [CI]: 1.04-1.70) and all ROIs combined (OR: 1.62; 95% CI: 1.14-2.29) correlated significantly with progression. None of the other clinicopathological/IHC variables correlated with progression., Conclusions and Clinical Implications: FAP is a potential prognostic biomarker for progression in high-risk NMIBC. FAP is a marker for cancer-associated fibroblasts and is linked to immunosuppression and neoangiogenesis, which makes future investigation clinically relevant., Patient Summary: We found that progression of high-risk non-muscle-invasive bladder cancer to muscle-invasive disease is less in patients with lower fibroblast activation protein-α (FAP) expression, which is a marker for cancer-associated fibroblasts., (© 2024 The Authors.)

Overuse of computed tomography pulmonary angiograms (CTPAs) for diagnosis of pulmonary embolism (PE) has been recognised as an issue for over ten years, with Choosing Wisely Australia recommending that CTPAs only be ordered if indicated by a clinical practice guideline (CPG). This study aimed to explore the use of evidence-based practice within regional Tasmanian emergency departments in relation to CTPA orders by determining whether CTPAs were ordered in accordance with validated CPGs. We conducted a retrospective medical record review of all patients who underwent CTPA across all public emergency departments in Tasmania between 1 August 2018 and 31 December 2019 inclusive. Data from 2758 CTPAs across four emergency departments were included. PE was reported in 343 (12.4%) of CTPAs conducted, with yield ranging from 8.2% to 16.1% between the four sites. Overall, 52.1% of participants had neither a CPG documented, nor a D-dimer conducted before their scan. A CPG was documented before 11.8% of scans, while D-dimer was conducted before 43% of CTPAs. The findings presented in this study indicate that Tasmanian emergency departments are not consistently 'Choosing Wisely' when investigating PE. Further research is required to identify explanations for these findings.

Healthcare workers are under increasing pressure to use limited resources more efficiently and improve patient outcomes. Healthcare redesign, a quality improvement methodology derived from the automotive industry, is a proven means of achieving these goals. Continuing Professional Development (CPD) opportunities for nurses seeking to build their capacity for healthcare redesign often come in the form of university courses, which can be costly and prohibitively time-consuming. We developed a Massive Open Online Course (MOOC) with a view to increasing the number of healthcare workers undertaking CPD in healthcare redesign and subsequently using these principles in their workplaces. The aim of the current study is to describe the development of our MOOC and its initial feedback from users. Materials and Methods: The theoretical and practical components of an existing postgraduate award course unit were made fit for purpose by being arranged into six weekly modules, before being transposed to an established learning management platform for MOOCs. Related quizzes, videos and interactive activities were then developed and included in each of these modules. Peer review of this content was completed by subject matter and teaching and learning experts prior to the MOOC being launched. Results: After running for nine months, 578 participants had enrolled in the MOOC, of whom 118 (20%) had followed through to completion. Participants were overwhelmingly from Australia (89%) and identified as female (78%). Preliminary feedback obtained from participants was positive, with 81% of respondents agreeing that they were satisfied with their experience, and 82% intending to apply their knowledge in practice. Conclusions: The MOOC has addressed a learning need by providing a brief and free form of education; learning from its development will help others seeking similar educational solutions. Initial feedback suggests the MOOC has been well-received and is likely to be translated into practice.

While altruism has been studied in healthcare professions such as nursing and medicine, the exploration of the characteristics of altruism, as related to paramedicine and emergency care in Australia, is limited. This scoping review explores altruism in paramedicine from the perspective of the paramedic as practitioner, learner, and educator as seen through the lens of the paramedic and the patient. Also discussed is the positive impact of altruism on the patient experience of care. A scoping review was used to assess the availability of data related to altruism in paramedicine. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews was used to guide the process. Search categories were orientated around the subject (altruism) and discipline (paramedicine). A total of 27 articles are included in this scoping review. Initial searching identified 742 articles; after duplicate removal, 396 articles were screened with 346 excluded. Fifty articles were full-text reviewed and 23 excluded. The final 27 were extracted following full-text screening. None of the articles are specific to altruism in paramedicine. The data related to the practice of altruism in paramedicine are extremely limited. The preponderance of data arise from Europe and North America which, due to crewing and service differences, may impact the practice of altruism in different regions. Recent changes to the scope of paramedic practice, workload, education, and case acuity may influence behaviour regarding altruism, compassion, caring, and associated caring behaviours. The practice and education of paramedics including altruism, compassion, caring and caring behaviours in the Australasian setting warrants further research.

Background: Neoadjuvant immunotherapies hold promise in muscle-invasive bladder cancer (MIBC)., Objective: To report on 2-yr disease-free (DFS) and overall (OS) survival including novel tissue-based biomarkers and circulating tumor DNA (ctDNA) in the ABACUS trial., Design, Setting, and Participants: ABACUS was a multicenter, single-arm, neoadjuvant, phase 2 trial, including patients with MIBC (T2-4aN0M0) who were ineligible for or refused neoadjuvant cisplatin-based chemotherapy., Intervention: Two cycles of atezolizumab were given prior to radical cystectomy. Serial tissue and blood samples were collected., Outcome Measurements and Statistical Analysis: The primary endpoints of pathological complete response (pCR) rate and dynamic changes to T-cell biomarkers were published previously. Secondary outcomes were 2-yr DFS and OS. A biomarker analysis correlated with relapse-free survival (RFS) was performed, which includes FOXP3, major histocompatibility complex class I, CD8/CD39, and sequential ctDNA measurements., Results and Limitations: The median follow-up time was 25 mo (95% confidence interval [CI] 25-26). Ninety-five patients received at least one cycle of atezolizumab. Eight patients did not undergo cystectomy (only one due to disease progression). The pCR rate was 31% (27/88; 95% CI 21-41). Two-year DFS and OS were 68% (95% CI 58-76) and 77% (95% CI 68-85), respectively. Two-year DFS in patients achieving a pCR was 85% (95% CI 65-94). Baseline PD-L1 and tumor mutational burden did not correlate with RFS (hazard ratio [HR] 0.60 [95% CI 0.24-1.5], p = 0.26, and 0.72 [95% CI 0.31-1.7], p = 0.46, respectively). RFS correlated with high baseline stromal CD8+ (HR 0.25 [95% CI 0.09-0.68], p = 0.007) and high post-treatment fibroblast activation protein (HR 4.1 [95% CI 1.3-13], p = 0.01). Circulating tumor DNA positivity values at baseline, after neoadjuvant therapy, and after surgery were 63% (25/40), 47% (14/30), and 14% (five/36), respectively. The ctDNA status was highly prognostic at all time points. No relapses were observed in ctDNA-negative patients at baseline and after neoadjuvant therapy. The lack of randomization and exploratory nature of the biomarker analysis are limitations of this work., Conclusions: Neoadjuvant atezolizumab in MIBC is associated with clinical responses and high DFS. CD8+ expression and serial ctDNA levels correlated with outcomes, and may contribute to personalized therapy in the future., Patient Summary: We showed that bladder cancer patients receiving immunotherapy followed by cystectomy have good long-term outcomes. Furthermore, we found that certain biological features can predict patients who might have particular benefit from this therapy., (Copyright © 2022 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

The Australian state of Tasmania has seen a spike in Emergency Department presentations in recent years, particularly among the elderly. A novel extended scope occupational therapy (ESOT) service was implemented by the Tasmanian Health Service, aimed at supporting hospital avoidance. Clients were referred to the ESOT service by other services after being assessed as having a high risk of imminent hospital presentation. Occupational Therapists provided short-term interventions related to falls, mobility, nutrition, and initiated onward referrals to other services. A convergent parallel mixed methods design was used to evaluate the ESOT service. Quantitative data from routinely collected administrative records and a purpose-built survey of referring clinicians were used alongside qualitative data from semi-structured interviews with clients/carers, to enable the triangulation of data. Quantitative data were analysed using descriptive statistics, while qualitative data collected in interviews were thematically analysed. A total of 104 extended scope interventions were provided to 100 clients. Most clients were able to stay at home. Qualitative data revealed that mobility, support, and facilitating access to support services were factors which added value to the client and carer experience. In conclusion, the ESOT program contributed to potentially avoiding hospital admissions and to improving the quality of life of participating clients.

Computed tomography pulmonary angiography (CTPA) has become the most widely used technique for diagnosis or exclusion of a pulmonary embolism (PE). It has been suggested that overuse of this imaging type may be prevalent, especially in emergency departments (EDs). The purpose of this literature review was to explore the use of CTPAs in EDs worldwide. A review following PRISMA guidelines was completed, with research published between September 2010 and August 2020 included. Five key topics emerged: use of CTPAs; explanations for overuse; use of D-dimer; variability in ordering practices between clinicians; and strategies to reduce overuse. This review found that CTPAs continue to be overused in EDs, leading to superfluous risks to patients. Published studies identify that while clinical practice guidelines (CPGs) have a strong effect on reducing unnecessary CTPAs with no significantly increased risk of missed diagnosis, the adoption of these tools by ED clinicians has remained low. This literature review highlights the need for further research into why CTPAs continue to be overused within EDs and why clinicians are hesitant to use CPGs in the clinical setting. Moreover, investigations into other potential strategies that may combat the overuse of this diagnostic tool are essential to reduce potential harm.

Objective: To understand the experiences of vulnerable clients who used telehealth during the Coronavirus pandemic., Design: The study employed a qualitative enquiry, utilising semi-structured interviews lasting 30-60 minutes with a thematic analysis approach to explore factors influencing client experience with telehealth., Setting: A wide range of locations across Tasmania, Australia., Participants: Twelve participants who were considered to be vulnerable on a number of domains, including: health and human wellbeing factors, social risk factors, functional limitations, and individual behavioural factors., Interventions: The provision of telehealth consultations to vulnerable clients., Main Outcome Measures: Four global themes were discovered: i) Telehealth saves time, money and energy; ii) User friendly technology facilitates care; iii) Rapport and confidentiality helps clients to feel safe; and iv) Fit for purpose telehealth provides a quality service., Results: The discovered themes entailed the major finding that most participants were satisfied with the overall quality of the telehealth service they received and the convenience of this service. Concerns were raised regarding the limitations around social interaction, physical examination, and access to fit-for-purpose telehealth devices., Conclusion: This research with vulnerable clients, from Tasmania, supports the evidence that the utilisation of telehealth allows more convenient access to care. To optimise the service, however, concerns regarding the desire for social interaction, appropriate physical examination, and access to fit-for-purpose telehealth devices will need to be addressed., (© 2022 The Authors. Australian Journal of Rural Health published by John Wiley & Sons Australia, Ltd on behalf of National Rural Health Alliance Ltd.)

Objective: The objective of this study was to measure humoral responses after SARS-CoV-2 vaccination in MS patients treated with ocrelizumab (OCR) compared to MS patients without disease modifying therapies (DMTs) in relation to timing of vaccination and B-cell count., Methods: OCR treated patients were divided into an early and a late group (cut-off time 12 weeks between infusion and first vaccination). Patients were vaccinated with mRNA-1273 (Moderna). B-cells were measured at baseline (time of first vaccination) and SARS-CoV-2 antibodies were measured at baseline, day 28, 42, 52 and 70., Results: 87 patients were included (62 OCR patients, 29 patients without DMTs). At day 70, seroconversion occurred in 39.3% of OCR patients compared to 100% of MS patients without DMTs. In OCR patients, seroconversion varied between 26% (early group) to 50% (late group) and between 27% (low B-cells) to 56% (at least 1 detectable B-cell/µL)., Conclusions: Low B-cell counts prior to vaccination and shorter time between OCR infusion and vaccination may negatively influence humoral response but does not preclude seroconversion. We advise OCR treated patients to get their first vaccination as soon as possible. In case of an additional booster vaccination, timing of vaccination based on B-cell count and time after last infusion may be considered., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

The histopathological growth patterns (HGPs) of liver metastases of colorectal cancer and of several other tumor types predict outcome of patients in multiple studies. The HGPs of liver metastases have a prognostic but also a predictive value with one of the growth patterns, the replacement growth pattern, related to resistance to systemic treatment. Given that the HGP can only be assessed in a reliable manner when a surgical resection of the metastasis has been performed, this biomarker cannot be exploited to the full. For example, HGPs can at this moment, not be used to decide whether patients with liver metastatic breast or colorectal cancer will benefit or not from locoregional treatment, such as surgery or radiotherapy, and from peri-operative systemic treatment. In this review we highlight studies that suggest that the HGPs of liver metastases can be identified by medical imaging. Although still to be confirmed by a prospective multicenter approach, some studies indeed achieve a high accuracy in predicting the HGPs by applying radiomic algorithms on CT- or MR-images of liver metastases. This is an important step towards a treatment planning of patients with liver metastatic cancer that takes into account the biology and the progression kinetics of the metastases., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective Clinicians across all health professions increasingly strive to add value to the care they deliver through the application of the central tenets of people-centred care (PCC), namely the 'right care', in the 'right place', at the 'right time' and 'tailored to the needs of communities'. This ideal is being hampered by a lack of a structured, evidence-based means to formulate policy and value the commissioning of services in an environment of increasing appreciation for the complex health needs of communities. This creates significant challenges for policy makers, commissioners and providers of health services. Communities face a complex intersection of challenges when engaging with healthcare. Increasingly, complexity is gaining prominence as a significant factor in the delivery of PCC. Based on the World Health Organization (WHO) components of health policy, this paper proposes a policy framework that enables policy makers, commissioners and providers of health care to integrate a model of complexity into policy, subsequent service planning and development of models of care. Methods The WHO components of health policy were used as the basis for the framework. Literature was drawn on to develop a policy framework that integrates complexity into health policy. Results Within the framework, complexity is juxtaposed between the WHO components of 'vision', 'priorities' and 'roles'. Conclusion This framework, supported by the literature, provides a means for policy makers and health planners to conduct analyses of and for policy. Further work is required to better model complexity in a manner that integrates consumer needs and provider capabilities. What is known about the topic? There is a growing body of evidence regarding patient complexity and its impact on the delivery of health services, but there is little consideration of patient complexity in policy, which is an important consideration for service provision. What does this paper add? This paper presents an argument for the inclusion of patient complexity in health policy and provides a framework for how that might occur. What are the implications for practitioners? The inclusion of patient complexity in policy could provide a means for policy makers to consider the factors that contribute to patient complexity in service provision decisions.

Influenza, a vaccine preventable disease, is a serious global public health concern which results in a considerable burden on the healthcare system. However, vaccine hesitancy is increasingly becoming a global problem. One prevalent misconception is that influenza vaccinations can cause the flu. We carried out this study to determine whether people undertaking influenza vaccination presented less with acute respiratory tract infection (ARTI) and influenza-like-illness (ILI) following vaccination. We utilised the Oxford Royal College of General Practitioners Research and Surveillance Centre sentinel database to examine English patients who received vaccination between 2014/2015 and 2018/2019. Of the 3,841,700 influenza vaccinations identified, vaccination details and primary care respiratory consultation counts were extracted to calculate the relative incidence (RI) per exposure risk period using the self-controlled case series methodology. Results showed a significant increase in the RI of respiratory consultation rates within fourteen days of vaccination across all five years. Less than 6.2% of vaccinations led to consultations for ARTI or ILI in primary care (crude consultation rate 6196 per 100,000). These findings, particularly if confirmed in further research, may reduce the risk of cross-infection between waiting patients and increase uptake of influenza vaccine.

Background: Pembrolizumab improves the survival of patients with advanced melanoma. A comprehensive analysis of baseline variables that predict the benefit of pembrolizumab monotherapy has not been conducted., Methods: Survival data of patients with advanced melanoma who were treated with pembrolizumab in a single university hospital were collected. A multivariate Cox regression analysis was performed to correlate baseline clinical, laboratory, and radiologic characteristics and NanoString IO360 gene expression profiling (GEP) with survival., Results: 183 patients were included (stage IV 85.2%, WHO performance status ≥1 31.1%; pembrolizumab first-line 25.7%), of whom 112 underwent baseline 18 F-FDG-PET/CT imaging, 58 had circulating tumor DNA (ctDNA) assessments, and GEP was available in 27 patients. Active brain metastases, a higher number of metastatic sites, lower albumin and absolute lymphocyte count (ALC), higher C-reactive protein (CRP) and neutrophil-to-lymphocyte ratio, higher total metabolic tumor volume (TMTV), and higher ctDNA levels were associated with worse survival. Elevated lactate dehydrogenase (LDH) ≥ 2ULN (upper limit of normal), CRP ≥ 10ULN, or ALC < 750/mm 3 delineate a subpopulation where treatment with pembrolizumab is futile. A TMTV ≥ 80 mL encompassed 17/21 patients with LDH ≥ 2ULN, CRP ≥ 10ULN, or ALC < 750/mm 3 . No significant associations were observed between baseline GEP scores and survival., Conclusion: Multiple baseline variables correlate with survival on pembrolizumab. TMTV is a more comprehensive baseline biomarker than CRP, LDH, or ALC in predicting the futility of pembrolizumab.

Background: Autologous monocyte-derived mRNA co-electroporated dendritic cells with mRNA encoding CD40 ligand (CD40L), CD70 and a constitutively activated TLR4 (caTLR4) (referred to as TriMixDC-MEL) have anti-tumor activity in advanced melanoma patients. We investigated the safety and activity of adjuvant TriMixDC-MEL in stage III/IV melanoma patients., Materials and Methods: Forty-one patients were randomly assigned to treatment with TriMixDC-MEL (n = 21) and standard follow-up (n = 20). "Cross-over" was allowed at the time of non-salvageable recurrence. The primary endpoint was the percentage of patients alive and disease-free at 1-year. For a subset of patients, (formalin-fixed paraffin-embedded), tumor tissue samples were available for mRNA expression profiling and PD-L1 immunohistochemical staining., Results: Baseline characteristics were well balanced. One-year after randomization, 71% of patients in the study arm were alive and free of disease compared to 35% in the control arm. After a median follow-up of 53 months (range 3-67), 23 patients experienced a non-salvageable melanoma recurrence (TriMixDC-Mel arm n = 9 and control arm n = 14).The median time to non-salvageable recurrence was superior in the TriMixDC-MEL arm (median 8 months (range 1-6) vs. not reached; log-rank p 0.044). TriMixDC-MEL-related adverse events (AE) consisted of transient local skin reactions, flu-like symptoms and post-infusion chills. No grade ≥ 3 AE's occurred. The mRNA expression profiling revealed four genes (STAT2, TPSAB1, CD9 and CSF2) as potential predictive biomarkers., Conclusion: TriMixDC-MEL id/iv as adjuvant therapy is tolerable and may improve the 1-year disease-free survival rate. Combination of optimized autologous monocyte-derived DC-formulations warrants further investigation in combination with currently approved adjuvant therapy options.

COVID-19 has had a significant impact on teaching and learning in postgraduate education. In particular, work integrated learning, in health care settings, has been disrupted in many ways negatively impacting student learning. Our Clinical Redesign courses are designed to deliver work-integrated learning in partnership with healthcare organisations to deliver workplace projects in real time, which has been complicated by COVID-19. This reflection examines the challenges that arose in the healthcare redesign teaching and learning space during the COVID-19 pandemic. We explore the experiences of our work-integrated learning students using Johns' reflection model. 1 Our students faced disruption to their education, workplaces and personal lives, and the experiences of our teaching team whose teaching philosophies were challenged. In response to the ongoing challenges, we developed strategies for supporting our students including the development of virtual projects for students who no longer had access to their workplaces or project appropriate resources., Competing Interests: Declaration of conflicting interests:The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2020.)

Healthcare organizations must continue to improve services to meet the rising demand and patient expectations. For this to occur, the health workforce needs to have knowledge and skills to design, implement, and evaluate service improvement interventions. Studies have shown that effective training in health service improvement and redesign combines didactic education with experiential project-based learning and on-the-ground coaching. Project-based learning requires organizational support and oversight, generally through executive sponsorship. A mixed-methods approach, comprising online surveys and semi-structured interviews, was used to explore the experiences of expert coaches and executive sponsors as key facilitators of workplace-based projects undertaken during an Australian postgraduate healthcare redesign course. Fifteen (54%) expert coaches and 37 (20%) executive sponsors completed the online survey. Ten expert coaches and six executive sponsors participated in interviews. The survey data revealed overall positive experiences for coaches and mixed experiences for sponsors. Interview participants expressed a sense of fulfillment that came from working with project teams to deliver a successful project and educational outcomes. However, concerns were raised about adequate resourcing, organizational recognition, competing priorities, and the skills required to effectively coach and sponsor. Expert coaches and executive sponsors sometimes felt under-valued and may benefit from cohort-tailored and evidence-based professional development.

Among visceral metastatic sites, cutaneous melanoma (CM) metastasises initially to the liver in ~14-20% of cases. Liver metastases in CM patients are associated with both poor prognosis and poor response to immunotherapy. Histopathological growth patterns (HGPs) of liver metastases of the replacement and desmoplastic type, particularly from colorectal cancer and uveal melanoma (UM), may impart valuable biological and prognostic information. Here, we have studied HGP in 43 CM liver metastases resected from 42 CM patients along with other prognostic factors from three institutions. The HGPs (replacement, desmoplastic, pushing) were scored at the metastasis-liver interface with two algorithms: (1) 100% desmoplastic growth pattern (dHGP) and any (≥1%) replacement pattern (any-rHGP) and (2) >50% dHGP, >50% rHGP or mixed (<50% dHGP and/or rHGP, pushing HGP). For 1 patient with 2 metastases, an average was taken to obtain 1 final HGP yielding 42 observations from 42 patients. 22 cases (52%) had 100% dHGP whereas 20 (48%) had any replacement. Cases with rHGP demonstrated vascular co-option/angiotropism. With the development of liver metastasis, only rHGP (both algorithms), male gender and positive resection margins predicted diminished overall survival (p = 0.00099 and p = 0.0015; p = 0.034 and p = 0.024 respectively). On multivariate analysis, only HGP remained significant. 7 of 42 (17%) patients were alive with disease and 21 (50%) died with follow-up after liver metastases ranging from 1.8 to 42.2 months (mean: 20.4 months, median: 19.0 months). 14 (33%) patients with previously-treated metastatic disease had no evidence of disease at last follow up. In conclusion, we report for the first time replacement and desmoplastic HGPs in CM liver metastases and their prognostic value, as in UM and other solid cancers. Of particular importance, any rHGP significantly predicted diminished overall survival while 100% dHGP correlated with increased survival. These results contribute to a better understanding of the biology of CM liver metastases and potentially may be utilised in managing patients with these metastases., (© 2020 The Authors. The Journal of Pathology: Clinical Research published by The Pathological Society of Great Britain and Ireland and John Wiley & Sons Ltd.)

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Transformational leadership (TL) is known to be essential to achieving Magnet ® recognition, an internationally prestigious status for nursing care excellence. Since its inception in the 1980s, empirical studies have identified benefits of implementing the Magnet ® Model involving improved patient care and nursing workforce outcomes. However, little is known about the leadership styles of nurse managers (NMs) working in a regional Australian context, which may hinder achieving Magnet ® status. To close the knowledge gap, a self-administered survey was conducted to measure leadership styles of NMs at a large health organization comprising hospitals with a wide range of service profiles in regional Australia using a validated tool-the Multifactor Leadership Questionnaire (MLQ-6S). One-way of variance (ANOVA) was used to identify statistical significance between respondents' demographic characteristics (e.g., age, education, gender) and their MLQ-6S scores. Respondents ( n = 78) reported their leadership styles as more transformational, compared to transactional or passive/avoidant leadership styles. The findings indicated that NMs' higher education ( p = 0.02) and older age ( p = 0.03) were associated with TL styles, whereas passive/avoidant leadership was generally reported by female ( p = 0.04) and younger ( p = 0.06) respondents. This study has identified differences in reported leadership styles among NMs, providing a unique organizational insight into developing strategies to improve NMs' TL, which could help to facilitate the implementation of the Magnet ® framework. Healthcare organizations in similar settings could benefit from replicating this study to identify a dominant leadership style and customize strategies to improve TL.

Antibodies targeting PD-1 or its ligand 1 PD-L1 such as atezolizumab, have great efficacy in a proportion of metastatic urothelial cancers 1,2 . Biomarkers may facilitate identification of these responding tumors 3 . Neoadjuvant use of these agents is associated with pathological complete response in a spectrum of tumors, including urothelial cancer 4-7 . Sequential tissue sampling from these studies allowed for detailed on-treatment biomarker analysis. Here, we present a single-arm phase 2 study, investigating two cycles of atezolizumab before cystectomy in 95 patients with muscle-invasive urothelial cancer (ClinicalTrials.gov identifier: NCT02662309). Pathological complete response was the primary endpoint. Secondary endpoints focused on safety, relapse-free survival and biomarker analysis. The pathological complete response rate was 31% (95% confidence interval: 21-41%), achieving the primary efficacy endpoint. Baseline biomarkers showed that the presence of preexisting activated T cells was more prominent than expected and correlated with outcome. Other established biomarkers, such as tumor mutational burden, did not predict outcome, differentiating this from the metastatic setting. Dynamic changes to gene expression signatures and protein biomarkers occurred with therapy, whereas changes in DNA alterations with treatment were uncommon. Responding tumors showed predominant expression of genes related to tissue repair after treatment, making tumor biomarker interpretation challenging in this group. Stromal factors such as transforming growth factor-β and fibroblast activation protein were linked to resistance, as was high expression of cell cycle gene signatures after treatment.

Background: Personalized targeted treatment in metastatic breast cancer relies on accurate assessment of molecular aberrations, e.g. overexpression of Human Epidermal growth factor Receptor 2 (HER-2). Molecular interrogation of circulating tumor cells (CTCs) can provide an attractive alternative for real-time biomarker assessment. However, implementation of CellSearch-based HER-2 analysis has been limited. Immunofluorescent (IF) image interpretation is crucial, as different HER-2 categories have been described. Major questions in CTC research are how these IF categories reflect gene expression and amplification, and if we should consider 'medium' HER-2 expressing CTCs for patient selection., Methods: Tumor cells from spiked cell lines (n = 8) and CTCs (n = 116 samples) of 85 metastatic breast cancer patients were enriched using CellSearch. Comparative analysis of HER-2 expression by IF imaging (ACCEPT, DEPArray, and visual scoring) with qRT-PCR and HER-2/neu FISH was performed., Results: Automated IF HER-2-profiling by DEPArray and ACCEPT delivered comparable results. There was a 98% agreement between 17 trained observers (visual scoring) and ACCEPT considering HER-2neg and HER-2high expressing CTCs. However, 89% of HER-2med expressing CTCs by ACCEPT were scored negative by observers. HER-2high expressing tumor cells demonstrated HER-2/neu gene amplification, whereas HER-2neg and HER-2med expressing tumor cells and CTCs by ACCEPT were copy-number neutral. All patients with HER-2-positive archival tumors had ≥1 HER-2high expressing CTCs, while 80% of HER-2-negative patients did not. High relative gene expression of HER-2 measured on enriched CTC lysates correlated with having ≥1 HER-2high expressing CTCs., Conclusion: Automated images analysis has enormous potential for clinical implementation. HER-2 characterization and clinical trial design should be focused on HER-2high expressing CTCs., Competing Interests: The authors DP, PJvD, ES, and AEM are affiliated with the company HistoGeneX NV. The company HistoGeneX NV provided support in the form of salaries for authors ES and AEM. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products to declare.

Evidence suggests that it is challenging for universities to develop workplace-relevant content and curricula by themselves, and this can lead to suboptimal educational outcomes. This paper examines the development, implementation, and evaluation of Australia's first tertiary graduate course in healthcare redesign, a partnership initiative between industry and university. The course not only provides students with an understanding of person-centered sustainable healthcare but also the skills and confidence to design, implement, and evaluate interventions to improve health service delivery. Increasing students' application of new knowledge has been through work-integrated learning, a pedagogy that essentially integrates theory with the practice of workplace application within a purposely designed curriculum. The specific aim of this study was to examine the outcomes of the course after two years, utilizing an anonymous online survey of graduates. Sixty-two graduates (48%) completed the survey. Kirkpatrick's four-level evaluation model was used to analyze the data. The analysis revealed high satisfaction levels in relation to the course content and delivery. Through successful completion of the innovative course, students had increased their knowledge of health system redesign methods and, importantly, the ability to translate that knowledge into everyday practice. Graduates of the clinical redesign course reported that they had been able to transfer their skills and knowledge to others in the workplace and lead further improvement projects.

Purpose: To infer the prognostic value of simultaneous androgen receptor ( AR ) and TP53 profiling in liquid biopsies from patients with metastatic castration-resistant prostate cancer (mCRPC) starting a new line of AR signaling inhibitors (ARSi). Experimental Design: Between March 2014 and April 2017, we recruited patients with mCRPC ( n = 168) prior to ARSi in a cohort study encompassing 10 European centers. Blood samples were collected for comprehensive profiling of CellSearch-enriched circulating tumor cells (CTC) and circulating tumor DNA (ctDNA). Targeted CTC RNA sequencing (RNA-seq) allowed the detection of eight AR splice variants (ARV). Low-pass whole-genome and targeted gene-body sequencing of AR and TP53 was applied to identify amplifications, loss of heterozygosity, mutations, and structural rearrangements in ctDNA. Clinical or radiologic progression-free survival (PFS) was estimated by Kaplan-Meier analysis, and independent associations were determined using multivariable Cox regression models., Results: Overall, no single AR perturbation remained associated with adverse prognosis after multivariable analysis. Instead, tumor burden estimates (CTC counts, ctDNA fraction, and visceral metastases) were significantly associated with PFS. TP53 inactivation harbored independent prognostic value [HR 1.88; 95% confidence interval (CI), 1.18-3.00; P = 0.008], and outperformed ARV expression and detection of genomic AR alterations. Using Cox coefficient analysis of clinical parameters and TP53 status, we identified three prognostic groups with differing PFS estimates (median, 14.7 vs. 7.51 vs. 2.62 months; P < 0.0001), which was validated in an independent mCRPC cohort ( n = 202) starting first-line ARSi (median, 14.3 vs. 6.39 vs. 2.23 months; P < 0.0001)., Conclusions: In an all-comer cohort, tumor burden estimates and TP53 outperform any AR perturbation to infer prognosis.See related commentary by Rebello et al., p. 1699., (©2018 American Association for Cancer Research.)

DNA demethylating agents may increase the immunogenicity of malignant tumours and increase the efficacy of subsequent treatment with immune check point inhibitors. We investigated the safety of administrating the demethylating agent decitabine by hepatic arterial infusionin patients with unresectable liver meta stases from solid tumours in a dose escalation phase I clinical trial. A total of nine eligible patients were enrolled and initiated study treatment at three different dose levels (two patients at 10, four at 15 and six at a dose level of 20mg decitabine/m2/day) (per protocol there was no intent to escalate the dose above the median tolerated intravenous dose level). Decitabine was administered as a 1-hour hepatic arterial infusion on five consecutive days every 4 weeks. Intrapatient dose escalation was applied in five patients. Grades 1 and 2 haematological toxicity was the most frequent treatment-related adverse event. None of the patients experienced treatment-limiting adverse events. Expression analysis of 30 cancer test is antigens (CTA) in pretreatment and post-treatment biopsies from patients indicated an increased expression of 21 CTAs after treatment. There were no objective tumour responses on study treatment or during post study exposure to immune checkpoint therapy in four patients with uveal melanoma liver metastases. We conclude that the investigate d hepatic arterial administration regimen for decitabine can be safely applied, and a dose level of 20 mg/m2/day on five consecutive days every 4 weeks can be considered for further investigation in combinatorial immunotherapy regimens., Trial Registration Number: NCT02316028., Competing Interests: Competing interests: None declared.

Background: There are multiple existing and emerging therapeutic avenues for metastatic prostate cancer, with a common denominator, which is the need for predictive biomarkers. Circulating tumor DNA (ctDNA) has the potential to cost-efficiently accelerate precision medicine trials to improve clinical efficacy and diminish costs and toxicity. However, comprehensive ctDNA profiling in metastatic prostate cancer to date has been limited., Methods: A combination of targeted and low-pass whole genome sequencing was performed on plasma cell-free DNA and matched white blood cell germline DNA in 364 blood samples from 217 metastatic prostate cancer patients., Results: ctDNA was detected in 85.9% of baseline samples, correlated to line of therapy and was mirrored by circulating tumor cell enumeration of synchronous blood samples. Comprehensive profiling of the androgen receptor (AR) revealed a continuous increase in the fraction of patients with intra-AR structural variation, from 15.4% during first-line metastatic castration-resistant prostate cancer therapy to 45.2% in fourth line, indicating a continuous evolution of AR during the course of the disease. Patients displayed frequent alterations in DNA repair deficiency genes (18.0%). Additionally, the microsatellite instability phenotype was identified in 3.81% of eligible samples (≥ 0.1 ctDNA fraction). Sequencing of non-repetitive intronic and exonic regions of PTEN, RB1, and TP53 detected biallelic inactivation in 47.5%, 20.3%, and 44.1% of samples with ≥ 0.2 ctDNA fraction, respectively. Only one patient carried a clonal high-impact variant without a detectable second hit. Intronic high-impact structural variation was twice as common as exonic mutations in PTEN and RB1. Finally, 14.6% of patients presented false positive variants due to clonal hematopoiesis, commonly ignored in commercially available assays., Conclusions: ctDNA profiles appear to mirror the genomic landscape of metastatic prostate cancer tissue and may cost-efficiently provide somatic information in clinical trials designed to identify predictive biomarkers. However, intronic sequencing of the interrogated tumor suppressors challenges the ubiquitous focus on coding regions and is vital, together with profiling of synchronous white blood cells, to minimize erroneous assignments which in turn may confound results and impede true associations in clinical trials.

Up to 50% of uveal melanomas (UM) metastasise to the liver within 10 years of diagnosis, and these almost always prove rapidly fatal. As histopathological growth patterns (HGPs) of liver metastases of the replacement and desmoplastic type, particularly from colon and breast carcinoma, may import valuable biological and prognostic information, we have studied HGP in a series of 41 UM liver metastases originating from 41 patients from the period 2006-2017. Twenty patients underwent enucleation while 21 had radiation therapy. Analysis of UM by array comparative genomic hybridisation revealed: 25 (64%) patients with high risk (monosomy3/8q gain); 13 (33%) intermediate risk (M3/8normal or disomy3/8q gain); and 1 low risk (disomy3/8normal). The principal HGP was replacement in 30 (73%) cases and desmoplastic in 11 (27%) cases. Cases with replacement demonstrated striking vascular co-option/angiotropism. With the development of liver metastasis, only the replacement pattern, largest primary tumour diameter, and R2 (incomplete resection) status predicted diminished overall survival (OS; p < 0.041, p < 0.017, p < 0.047, respectively). On multivariate analysis, only HGP (hazard ratio; HR = 6.51, p = 0.008) and resection status remained significant. The genomic high-risk variable had no prognostic value at this stage of liver metastasis. Chi-square test showed no association of HGP with monosomy 3 or 8q gain. Eighteen of 41 (44%) patients are alive with disease and 23 (56%) patients died with follow-up ranging from 12 to 318 months (mean: 70 months, median: 47 months). In conclusion, we report for the first time the frequency of the replacement and desmoplastic HGPs in liver UM metastases resected from living patients, and their potential important prognostic value for UM patients, as in other solid cancers. These results may potentially be utilised to develop radiological correlates and therapeutic targets for following and treating patients with UM metastases., (© 2018 The Authors. The Journal of Pathology: Clinical Research published by The Pathological Society of Great Britain and Ireland and John Wiley & Sons Ltd.)

The encroachment of a growing tumor upon the cells and structures of surrounding normal tissue results in a series of histopathological growth patterns (HGPs). These morphological changes can be assessed in hematoxylin-and-eosin (H&E) stained tissue sections from primary and metastatic tumors and have been characterized in a range of tissue types including liver, lung, lymph node and skin. HGPs in different tissues share certain general characteristics like the extent of angiogenesis, but also appropriate tissue-specific mechanisms which ultimately determine differences in the biology of HGP subtypes. For instance, in the well-characterized HGPs of liver metastases, the two main subtypes, replacement and desmoplastic, recapitulate two responses of the normal liver to injury: regeneration and fibrosis. HGP subtypes have distinct cytokine profiles and differing levels of lymphocytic infiltration which suggests that they are indicative of immune status in the tumor microenvironment. HGPs predict response to bevacizumab and are associated with overall survival (OS) after surgery for liver metastases in colorectal cancer (CRC). In addition, HGPs can change over time in response to therapy. With standard scoring methods being developed, HGPs represent an easily accessible, dynamic biomarker to consider when determining strategies for treatment using anti-VEGF and immunomodulatory drugs., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: The outcome to treatment administered to patients with metastatic castration-resistant prostate cancer (mCRPC) greatly differs between individuals, underlining the need for biomarkers guiding treatment decision making., Objective: To investigate the prognostic value of circulating tumor cell (CTC) enumeration and dynamics, in the context of second-line endocrine therapies (ie, abiraterone acetate or enzalutamide), irrespective of prior systemic therapies., Design, Settings, and Participants: In a prospective, multicentre study blood samples for CTC enumeration were collected from patients with mCRPC at baseline (n = 174). In patients who responded for minimally 10-12 weeks a follow-up sample was collected., Outcome Measurements and Statistical Analysis: For baseline analysis, patients were stratified in <5 or ≥5 CTCs/7.5 mL, whereas for the analysis of CTC dynamics at 10-12 weeks, in patients with stable, increasing or decreasing CTC counts. Progression-free survival (PFS), overall survival (OS), and PSA changes at 10-12 weeks were compared between groups., Results: Patients demonstrating increasing CTCs on therapy had a shorter median PFS (4.03 vs 12.98 vs 13.67 months, HR 3.6, 95%CI 1.9-6.8; P < 0.0001) and OS (11.2 months vs not reached, HR 9.5, 95%CI 3.7-24; P < 0.0001), compared to patients with decreasing or stable CTCs. Multivariable Cox regression showed that prior chemotherapy (HR 4.1, 95%CI 1.9-8.9; P = 0.0003), a high baseline CTC count (HR 1.5, 95%CI 1.2-1.9; P = 0.002) and increasing CTCs at follow-up (HR 3.3, 95%CI 1.4-7.6; P = 0.005) were independent predictors of worse PFS. Previous chemotherapy (HR 7, 95%CI 1.9-25; P = 0.003), high baseline CTC counts (HR 2.2, 95%CI 1.4-3.7; P = 0.002) and increasing CTCs during therapy (HR 4.6, 95%CI 1.4-15; P = 0.01) were independently associated with shorter OS. ≥30% and ≥50% PSA responses less frequently occurred in patients with CTC inclines at 10-12 weeks on therapy (χ 2 test: P < 0.01)., Conclusions: CTC dynamics during therapy are associated with PSA response and provide independent clinical prognostication over PSA declines. Hence the study demonstrates the pharmacodynamic properties of CTCs., (© 2018 Wiley Periodicals, Inc.)

Background: Liver metastases present with distinct histopathological growth patterns (HGPs), including the desmoplastic, pushing and replacement HGPs and two rarer HGPs. The HGPs are defined owing to the distinct interface between the cancer cells and the adjacent normal liver parenchyma that is present in each pattern and can be scored from standard haematoxylin-and-eosin-stained (H&E) tissue sections. The current study provides consensus guidelines for scoring these HGPs., Methods: Guidelines for defining the HGPs were established by a large international team. To assess the validity of these guidelines, 12 independent observers scored a set of 159 liver metastases and interobserver variability was measured. In an independent cohort of 374 patients with colorectal liver metastases (CRCLM), the impact of HGPs on overall survival after hepatectomy was determined., Results: Good-to-excellent correlations (intraclass correlation coefficient >0.5) with the gold standard were obtained for the assessment of the replacement HGP and desmoplastic HGP. Overall survival was significantly superior in the desmoplastic HGP subgroup compared with the replacement or pushing HGP subgroup (P=0.006)., Conclusions: The current guidelines allow for reproducible determination of liver metastasis HGPs. As HGPs impact overall survival after surgery for CRCLM, they may serve as a novel biomarker for individualised therapies.

Aim of the Study: The European Society of Breast Cancer Specialists (EUSOMA) has fostered a voluntary certification process for breast centres to establish minimum standards and ensure specialist multidisciplinary care. Prospectively collected anonymous information on primary breast cancer cases diagnosed and treated in the units is transferred annually to a central EUSOMA data warehouse for continuous monitoring of quality indicators (QIs) to improve quality of care. Units have to comply with the EUSOMA Breast Centre guidelines and are audited by peers. The database was started in 2006 and includes over 110,000 cancers from breast centres located in Germany, Switzerland, Belgium, Austria, The Netherlands, Spain, Portugal and Italy. The aim of the present study is assessing time trends of QIs in EUSOMA-certified breast centres over the decade 2006-2015., Materials and Methods: Previously defined QIs were calculated for 22 EUSOMA-certified breast centres (46122 patients) during 2006-2015., Results: On the average of all units, the minimum standard of care was achieved in 8 of 13 main EUSOMA QIs in 2006 and in all in 2015. All QIs, except removal of at least 10 lymph nodes at axillary clearance and oestrogen receptor-negative tumours (T > 1 cm or N+) receiving adjuvant chemotherapy, improved significantly in this period. The desirable target was reached for two QIs in 2006 and for 7 of 13 QIs in 2015., Conclusion: The EUSOMA model of audit and monitoring QIs functions well in different European health systems and results in better performance of QIs over the last decade. QIs should be evaluated and adapted on a regular basis, as guidelines change over time., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Expression of the androgen receptor splice variant 7 (AR-V7) is associated with poor response to second-line endocrine therapy in castration-resistant prostate cancer (CRPC). However, a large fraction of nonresponding patients are AR-V7-negative., Objective: To investigate if a comprehensive liquid biopsy-based AR profile may improve patient stratification in the context of second-line endocrine therapy., Design, Setting, and Participants: Peripheral blood was collected from patients with CRPC (n=30) before initiation of a new line of systemic therapy. We performed profiling of circulating tumour DNA via low-pass whole-genome sequencing and targeted sequencing of the entire AR gene, including introns. Targeted RNA sequencing was performed on enriched circulating tumour cell fractions to assess the expression levels of seven AR splice variants (ARVs)., Outcome Measurements and Statistical Analysis: Somatic AR variations, including copy-number alterations, structural variations, and point mutations, were combined with ARV expression patterns and correlated to clinicopathologic parameters., Results and Limitations: Collectively, any AR perturbation, including ARV, was detected in 25/30 patients. Surprisingly, intra-AR structural variation was present in 15/30 patients, of whom 14 expressed ARVs. The majority of ARV-positive patients expressed multiple ARVs, with AR-V3 the most abundantly expressed. The presence of any ARV was associated with progression-free survival after second-line endocrine treatment (hazard ratio 4.53, 95% confidence interval 1.424-14.41; p=0.0105). Six out of 17 poor responders were AR-V7-negative, but four carried other AR perturbations., Conclusions: Comprehensive AR profiling, which is feasible using liquid biopsies, is necessary to increase our understanding of the mechanisms underpinning resistance to endocrine treatment., Patient Summary: Alterations in the androgen receptor are associated with endocrine treatment outcomes. This study demonstrates that it is possible to identify different types of alterations via simple blood draws. Follow-up studies are needed to determine the effect of such alterations on hormonal therapy., (Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

An in silico pathway analysis was performed in order to improve current knowledge on the molecular drivers of cervical cancer and detect potential targets for treatment. Three publicly available Affymetrix gene expression data-sets (GSE5787, GSE7803, GSE9750) were retrieved, vouching for a total of 9 cervical cancer cell lines (CCCLs), 39 normal cervical samples, 7 CIN3 samples and 111 cervical cancer samples (CCSs). Predication analysis of microarrays was performed in the Affymetrix sets to identify cervical cancer biomarkers. To select cancer cell-specific genes the CCSs were compared to the CCCLs. Validated genes were submitted to a gene set enrichment analysis (GSEA) and Expression2Kinases (E2K). In the CCSs a total of 1,547 probe sets were identified that were overexpressed (FDR < 0.1). Comparing to CCCLs 560 probe sets (481 unique genes) had a cancer cell-specific expression profile, and 315 of these genes (65%) were validated. GSEA identified 5 cancer hallmarks enriched in CCSs (P < 0.01 and FDR < 0.25) showing that deregulation of the cell cycle is a major component of cervical cancer biology. E2K identified a protein-protein interaction (PPI) network of 162 nodes (including 20 drugable kinases) and 1626 edges. This PPI-network consists of 5 signaling modules associated with MYC signaling (Module 1), cell cycle deregulation (Module 2), TGFβ-signaling (Module 3), MAPK signaling (Module 4) and chromatin modeling (Module 5). Potential targets for treatment which could be identified were CDK1, CDK2, ABL1, ATM, AKT1, MAPK1, MAPK3 among others. The present study identified important driver pathways in cervical carcinogenesis which should be assessed for their potential therapeutic drugability.

Background: The enumeration of circulating tumour cells (CTCs) with the EpCAM-based CellSearch system has prognostic significance in patients with metastatic breast cancer (MBC). The aim of this study was to explore potential differences in the detection and prognostic significance of CTCs in MBC according to immunohistochemical subtypes of breast cancer., Methods: CellSearch CTC counts were obtained from 154 MBC patients before first-line systemic treatment between November 2007 and August 2012. Patients were categorised in five subgroups according to immunohistochemical surrogate definitions of intrinsic subtypes in breast cancer based on hormone receptor status, HER2/neu status and histological grade. Differences in progression-free (PFS) and overall survival (OS) were assessed relative to the cut-off value of ≥5 CTCs per 7.5 ml blood., Results: No significant differences were observed in the absolute CTC counts (P=0.120) or in CTC positivity rates according to ≥1 and ≥5 CTCs per 7.5 ml blood detection thresholds (P=0.165 and P=0.651, respectively) between immunohistochemical subtypes. However, very high CTC counts, defined as ≥80 CTCs per 7.5 ml, were observed more frequently in patients with Luminal A and triple negative (TN) breast cancer (P=0.024). In the total study population, the presence of ≥5 CTCs was the single most significant prognostic factor for both PFS and OS in multivariate analysis (P<0.001). A more limited prognostic impact, not reaching statistical significance, was observed in patients with HER2-positive disease as opposed to patients with Luminal A, Luminal B-HER2-negative and TN disease., Conclusion: The detection of EpCAM+CTCs was not clearly associated with any of the immunohistochemical subtypes of breast cancer in patients with MBC before first-line treatment. Potentially clinically relevant differences were however observed at very high CTC counts. Furthermore, our data suggest a lower prognostic significance of CTC evaluation in HER2-positive patients with MBC.

Background: The enumeration of circulating tumour cells (CTC) has prognostic significance in patients with metastatic breast cancer (MBC) and monitoring of CTC levels over time has considerable potential to guide treatment decisions. However, little is known on CTC kinetics in the human bloodstream., Methods: In this study, we compared the number of CTC in both 7.5 ml central venous blood (CVB) and 7.5 ml peripheral venous blood (PVB) from 30 patients with MBC starting with a new line of chemotherapy., Results: The number of CTC was found to be significantly higher in CVB (median: 43.5; range: 0-4036) than in PVB (median: 33; range: 0-4013) (P=0.001). When analysing samples pairwise, CTC counts were found to be significantly higher in CVB than in PVB in 12 out of 26 patients with detectable CTC. In contrast, only 2 out of 26 patients had higher CTC counts in PVB as compared with CVB, whereas in 12 remaining patients no significant difference was seen. The pattern of CTC distribution was independent of the sites of metastatic involvement., Conclusion: A substantial difference in the number of CTC was observed between CVB and PVB of patients with MBC. Registration of the site of blood collection is warranted in studies evaluating the role of CTC assessment in these patients.

The exponential use of robotic surgery is not the result of evidence-based benefits but mainly driven by the manufacturers, patients and enthusiastic surgeons. The present review of the literature shows that robot-assisted surgery is consistently more expensive than video-laparoscopy and in many cases open surgery. The average additional variable cost for gynecological procedures was about 1600 USD, rising to more than 3000 USD when the amortized cost of the robot itself was included. Generally most robotic and laparoscopic procedures have less short-term morbidity, blood loss, intensive care unit, and hospital stay than open surgery. Up to now no major consistent differences have been found between robot-assisted and classic video-assisted procedures for these factors. No comparative data are available on long-term morbidity and oncologic outcome after open, robotic, and laparoscopic gynecologic surgery. It seems that currently only for very complex surgical procedures, such as cardiac surgery, the costs of robotics can be competitive to open surgical procedures. In order to stay viable, robotic programs will need to pay for themselves on a per case basis and the costs of robotic surgery will have to be reduced.

The first case of robotic-assisted laparoscopic cytoreductive surgery for a metastatic malignant ovarian tumor is described. A 65-year-old woman who was treated for breast cancer 13 years earlier presented with a deep venous thrombosis in the right leg and a pelvic mass. Imaging tests showed bilateral solid ovarian tumors and an enlarged lymph node at the level of the right common iliac vessels but no evidence of any other tumor metastases. The patient was offered and accepted to undergo a da Vinci robotic-assisted bilateral adnexectomy with hysterectomy and pelvic lymph node sampling. The surgery took 200 minutes, and the patient was discharged uneventfully on the third postoperative day. Histologic examination showed strongly estrogen receptor-positive metastatic lobular carcinoma of the breast in both ovaries and fallopian tubes. She was further treated with adjuvant exemestane and is currently doing well. It is possible to treat selected patients with malignant ovarian tumors by robotic-assisted laparoscopy.

Purpose: Lymph node (LN) lymphangiogenesis has recently been shown to be important in the premetastatic niche of sentinel LNs. To study its role in the further metastatic spread of human breast cancer, we investigated the association of angiogenesis and lymphangiogenesis in sentinel LN metastases with the presence of nonsentinel LN metastases in breast cancer patients with a positive sentinel LN., Experimental Design: Angiogenesis and lymphangiogenesis--quantified as endothelial cell proliferation fraction (ECP%) and lymphatic ECP fraction (LECP%)--were assessed in sentinel LN metastases of 65 T(1)/T(2) patients with breast cancer using CD34/Ki67 and D2-40/Ki67 immunohistochemical double stains. Correlations were analyzed between nonsentinel LN status, LECP%, and other clinicopathologic variables (number of involved sentinel LNs, size of the primary tumor and LN metastasis, presence of lymphovascular invasion in the primary tumor, and of extracapsular growth in the sentinel LN metastasis)., Results: Thirty seven out of 65 patients (56.9%) had at least one involved nonsentinel LN. Size of the sentinel LN metastasis (P = 0.001), lymphovascular invasion (P = 0.02), extracapsular growth (P = 0.02), and LECP% (P = 0.01) were correlated with a positive nonsentinel LN status. The multivariate logistic regression model retained high LECP% (odds ratios = 4.2, P = 0.01) and the presence of extracapsular growth (odds ratios = 3.38, P = 0.04) as independently associated with the presence of nonsentinel LN metastases., Conclusions: Increased sentinel LN metastasis lymphangiogenesis is associated with metastatic involvement of nonsentinel axillary LNs. These are the first data sustaining the hypothesis that sentinel LN lymphangiogenesis is involved in further metastatic spread of human breast cancer.

This is the first article reporting sentinel node identification in a patient with endometrial cancer recurring in the vagina. A 79-year-old woman presented with a midvaginal recurrence of a stage IB, grade II endometroid carcinoma that had been treated 3 years earlier by a total abdominal hysterectomy, bilateral salpingoophorectomy, and pelvic lymph node sampling, followed by adjuvant brachytherapy to the vaginal vault. A staging examination under anesthetic was performed. Preoperatively, 60-MBq technetium-labeled nannocolloid was injected in the mucosa at 3, 6, 9, and 12 o'clock just adjacent to the tumor recurrence. Three sentinel nodes were detected, respectively, in the left obturator fossa (two) and the right external iliac region, using a laparoscopic probe (Navigator) and removed for pathological assessment. As they proved to be negative, the patient underwent a total vaginectomy, parametrectomy with pelvic lymphadenectomy. The tumor was completely removed, and all lymph nodes proved to be negative. The accuracy of sentinel node identification in patients with recurrent gynecological tumors needs further evaluation. This unique case shows that sentinel node detection is possible after previous radiotherapy and surgery and hopes to stimulate further research in this field.

Objective: The objective was to describe sentinel ode detection in patients with primary and recurrent vaginal carcinoma., Method: Preoperatively 60-mBq technetium-labeled nannocolloid was injected in the mucosa at 3, 6, 9, and 12 o'clock, just adjacent to the vaginal cancer. Sentinel nodes were detected using a laparoscopic or hand-held probe (Navigator) and removed for pathological assessment., Results: Sentinel nodes could be found in two of three patients with primary stage I or II carcinoma of the vagina. In the first patient the sentinel nodes, located in the groin and obturator region, proved to be negative and she was treated with a wide local excision of the tumor, pelvic and groin lymphadenectomy, and adjuvant radiotherapy. The second patient had tumor metastases in the sentinel node, which was found just below of the junction of the iliac vessels, and she underwent combined chemo- and radiotherapy. In a third patient no sentinel node could be detected at lymphoscintigraphy. A last patient with stage III carcinoma of the upper vagina was initially treated by combined chemo-radiotherapy but recurred 6 months later. During a staging procedure the sentinel nodes could be detected in the right obturator fossa and were removed laparoscopically. As they were negative, she underwent a posterior pelvic exenteration with complete resection of the tumor., Conclusion: Laparoscopic detection of sentinel nodes using 99mTc-labeled colloid is feasible in patients with primary and recurrent vaginal cancer and may provide important information to direct further management.

A high-frequency EPR study is presented of the integer spin system Ni(II) in the host of Zn-tris(ethylenediamine) dinitrate. This complex shows a broad structureless line at X band. At D band (130 GHz) however, a standard triplet powder spectrum is observed. Superimposed on this spectrum is a "double-quantum" line at the expected position. The microwave power dependency of this line is found to be in contradiction with existing theory on multiple-quantum transitions. The line in our spectra shows a single quantum line behavior in intensity and linewidth as a function of the microwave frequency from 35 to 130 GHz. A literature survey leads to the conclusion that most double-quantum features in high-spin systems do not follow the P3/2 power dependency predicted by second-order perturbation theory. In our case the double-quantum line is assigned to an enhancement effect due to the simultaneous excitation of two single-quantum transitions. Copyright 1998 Academic Press. Copyright 1998 Academic Press

The active H-cluster of the Fe-hydrogenases from Megasphaera elsdenii and Desulfovibrio vulgaris (strain Hildenborough) has been investigated with one- and two-dimensional pulsed EPR spectroscopy. In both complexes the coordination of a nitrogen-containing ligand was found. The unusual quadrupole interaction parameters (D. vulgaris: quadrupole coupling constant, K = 1.20 MHz, asymmetry parameter eta = 0.32, M. elsdenii: K = 1.23 MHz, eta = 0.25) indicate a non-protein type of nitrogen and are consistent with cyanide as ligand to the H-cluster. The additional interactions measured on the EPR signal of the inactivated H-cluster in D. vulgaris hydrogenase are consistent with an imidazole interaction similar to that found in Rieske-type iron-sulfur clusters. Since a His residue near the putative H-cluster binding motif of Cys residues, His371, is the only conserved His in Fe-hydrogenases, it is a likely candidate for the base that accepts the proton in the heterolytic cleavage of molecular hydrogen. The inactivation of the enzyme is accompanied by direct binding of the imidazole ring to the H-cluster.