Publications by authors named "Janet Brown"

135 Publications

Correlation between targeted RNAseq signature of breast cancer CTCs and onset of bone-only metastases.

Br J Cancer 2021 Jul 16. Epub 2021 Jul 16.

Department of Biomedical Sciences and Human Oncology-Section of Internal Medicine and Clinical Oncology, University of Bari Aldo Moro, Bari, Italy.

Background: Bone is the most frequent site of metastases from breast cancer (BC), but no biomarkers are yet available to predict skeletal dissemination.

Methods: We attempted to identify a gene signature correlated with bone metastasis (BM) onset in circulating tumour cells (CTCs), isolated by a DEPArray-based protocol from 40 metastatic BC patients and grouped according to metastasis sites, namely "BM" (bone-only), "ES" (extra-skeletal) or BM + ES (bone + extra-skeletal).

Results: A 134-gene panel was first validated through targeted RNA sequencing (RNAseq) on sub-clones of the MDA-MB-231 BC cell line with variable organotropism, which successfully shaped their clustering. The panel was then applied to CTC groups and, in particular, the "BM" vs "ES" CTC comparison revealed 31 differentially expressed genes, including MAF, CAPG, GIPC1 and IL1B, playing key prognostic roles in BC.

Conclusion: Such evidence confirms that CTCs are suitable biological sources for organotropism investigation through targeted RNAseq and might deserve future applications in wide-scale prospective studies.
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http://dx.doi.org/10.1038/s41416-021-01481-zDOI Listing
July 2021

Embedding supervised exercise training for men on androgen deprivation therapy into standard prostate cancer care: a feasibility and acceptability study (the STAMINA trial).

Sci Rep 2021 06 14;11(1):12470. Epub 2021 Jun 14.

Allied Health Professionals, Radiotherapy and Oncology, Sheffield Hallam University, Sheffield, UK.

Lifestyle interventions involving exercise training offset the adverse effects of androgen deprivation therapy in men with prostate cancer. Yet provision of integrated exercise pathways in cancer care is sparse. This study assessed the feasibility and acceptability of an embedded supervised exercise training intervention into standard prostate cancer care in a single-arm, multicentre prospective cohort study. Feasibility included recruitment, retention, adherence, fidelity and safety. Acceptability of behaviourally informed healthcare and exercise professional training was assessed qualitatively. Despite the imposition of lockdown for the COVID-19 pandemic, referral rates into and adherence to, the intervention was high. Of the 45 men eligible for participation, 79% (n = 36) received the intervention and 47% (n = 21) completed the intervention before a government mandated national lockdown was enforced in the United Kingdom. Patients completed a mean of 27 min of aerobic exercise per session (SD = 3.48), at 77% heart rate maximum (92% of target dose), and 3 sets of 10 reps of 3 resistance exercises twice weekly for 12 weeks, without serious adverse event. The intervention was delivered by 26 healthcare professionals and 16 exercise trainers with moderate to high fidelity, and the intervention was deemed highly acceptable to patients. The impact of societal changes due to the pandemic on the delivery of this face-to-face intervention remain uncertain but positive impacts of embedding exercise provision into prostate cancer care warrant long-term investigation.
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http://dx.doi.org/10.1038/s41598-021-91876-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203669PMC
June 2021

Natural history of stage II/III breast cancer, bone metastasis and the impact of adjuvant zoledronate on distribution of recurrences.

J Bone Oncol 2021 Jun 4;28:100367. Epub 2021 May 4.

Department of Oncology and Metabolism, University of Sheffield Medical School, Sheffield, United Kingdom.

Aim: The prognosis for women with breast cancer has improved markedly over recent decades. However, mortality from breast cancer remains high and, for those developing metastatic disease, curative therapy is not possible. Here, we report the frequency and distribution of disease recurrence(s) in a large population of women with AJCC stage II/III breast cancer and evaluate the impact of adjuvant treatment with the bisphosphonate zoledronate on clinical outcomes.

Patients And Methods: In the context of the AZURE study (ISRCTN7981382), 3359 patients with histologically confirmed stage II/III breast cancer were randomised to receive standard adjuvant treatment ± zoledronate for five years. Patients were followed up for 10 years and all patients with recurrent disease in that time identified. The site of first recurrence, the first distant recurrence site(s) and bone metastasis at any time were recorded and outcomes in the control and zoledronate treatment groups compared. Survival after recurrence was also evaluated.

Results: In the study population as a whole, disease recurrence at a median follow-up of 117 months occurred in 1010/3359 (30%) women with a relatively constant rate of disease relapse of around 3% per year. 727 (72%) first recurrences were at distant sites, 178 locoregional (18%) and 105 (10%) both locoregional and distant relapses occurred synchronously. Bone was the most frequent first recurrence site occurring in 463 (14%) of all patients and was the only distant metastatic site in 265 (7.9%). 69% of the control group who developed recurrent disease had bone metastases identified. Bone metastases were more frequent in those with oestrogen receptor (ER) positive disease and recurrences overall, especially at visceral sites, were more likely with ER negative disease. Zoledronate reduced bone metastases in both ER subgroups but increased the proportion with extra-skeletal metastases, particularly in women who were not definitely postmenopausal at study entry. Adjuvant zoledronate also reduced bone metastases after recurrence at an extra-skeletal site.

Conclusions: This analysis provides contemporary information on the frequency and pattern of recurrences after treatment for stage II/III breast cancer that may be of value in planning future adjuvant trials. It confirms the ongoing importance of bone metastases and describes in detail for the first time the effects of adjuvant zoledronate on the pattern of metastasis.
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http://dx.doi.org/10.1016/j.jbo.2021.100367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134065PMC
June 2021

Interleukin-1 receptor antagonist: An exploratory plasma biomarker that correlates with disability and provides pathophysiological insights in relapsing-remitting multiple sclerosis.

Mult Scler Relat Disord 2021 Jul 7;52:103006. Epub 2021 May 7.

Division of Biomedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, 300 Prince Philip Drive, St. John's, A1B 3V6 Newfoundland and Labrador, Canada; Discipline of Medicine (Neurology), Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada. Electronic address:

Background: Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disorder. Interleukin-1 receptor antagonist (IL-1RA) is an endogenous soluble antagonist of the IL-1 receptor and blocks the pro-inflammatory effects of IL-1β known to contribute to MS pathology. The objectives of this study were to determine whether IL-1RA is associated with disability in MS and how this correlates with neurofilament light (NfL) levels in cerebrospinal fluid (CSF).

Methods: Peripheral blood and CSF were collected from consenting MS patients. Patient demographic and clinical variables, including past relapse activity, were also collected. Circulating levels of IL-1RA, IL-18, and IL-1β were measured in plasma; IL-1RA and NfL were measured in the CSF via Bio-plex multiplex immunoassay kits and ELISA, respectively. IL-1RA expression was investigated in vitro using primary human macrophages and microglia, and in situ using post-mortem MS tissue.

Results: Following a multiple regression analysis, IL-1RA levels in plasma correlated with expanded disability status scale score independent of all other variables. In a separate cohort, CSF IL-1RA significantly correlated with NfL. In vitro, induction of the NLRP3 inflammasome, a pathological hallmark within MS lesions, led to increased release of IL-1RA from primary human microglia and macrophages. In the CNS, IL-1RA macrophages/microglia were present at the rim of mixed active/inactive MS lesions.

Conclusions: Results presented in this study demonstrate that IL-1RA is a novel exploratory biomarker in relapsing-remitting MS, which correlates with disability and provides mechanistic insights into the regulatory inflammatory responses within the demyelinated CNS.
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http://dx.doi.org/10.1016/j.msard.2021.103006DOI Listing
July 2021

The development of a theory and evidence-based intervention to aid implementation of exercise into the prostate cancer care pathway with a focus on healthcare professional behaviour, the STAMINA trial.

BMC Health Serv Res 2021 Mar 25;21(1):273. Epub 2021 Mar 25.

Institute for Population Health Sciences, Queen Mary, University of London, London, UK.

Background: Twice-weekly supervised aerobic and resistance exercise for 12 weeks reduces fatigue and improves quality of life in men on Androgen Deprivation Therapy for prostate cancer. Despite the National Institute for Health and Care Excellence (NICE) proposing this as standard of care, it does not routinely take place in practice. Healthcare professionals are in a prime position to deliver and integrate these recommendations. A change in the behaviour of clinical teams is therefore required. In this paper, we describe the development of a training package for healthcare professionals using theory and evidence to promote delivery of such recommendations as standard care.

Methods: The intervention development process was guided by the Medical Research Council guidance for complex interventions and the Behaviour Change Wheel. Target behaviours were identified from the literature and thirty-five prostate cancer care healthcare professionals (including oncologists, consultant urologists, clinical nurse specialists, physiotherapists, general practitioners and commissioners) were interviewed to understand influences on these behaviours. The Theoretical Domains Framework was used to identify theoretical constructs for change. Behaviour change techniques were selected based on theory and evidence and were translated into intervention content. The intervention was refined with the input of stakeholders including healthcare professionals, patients, and exercise professionals in the form of rehearsal deliveries, focus groups and a workshop.

Results: Seven modifiable healthcare professional target behaviours were identified to support the delivery of the NICE recommendations including identifying eligible patients suitable for exercise, recommending exercise, providing information, exercise referral, providing support and interpret and feedback on progress. Ten domains from the Theoretical Domain's Framework were identified as necessary for change, including improving knowledge and skills, addressing beliefs about consequences, and targeting social influences. These were targeted through twenty-two behaviour change techniques delivered in a half-day, interactive training package. Based on initial feedback from stakeholders, the intervention was refined in preparation for evaluation.

Conclusions: We designed an intervention based on theory, evidence, and stakeholder feedback to promote and support the delivery of NICE recommendations. Future work will aim to test this training package in a multi-centre randomised trial. If proven effective, the development and training package will provide a template for replication in other clinical populations, where exercise has proven efficacy but is insufficiently implemented.
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http://dx.doi.org/10.1186/s12913-021-06266-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992804PMC
March 2021

Towards implementing exercise into the prostate cancer care pathway: development of a theory and evidence-based intervention to train community-based exercise professionals to support change in patient exercise behaviour (The STAMINA trial).

BMC Health Serv Res 2021 Mar 22;21(1):264. Epub 2021 Mar 22.

Institute for Population Health Sciences, Queen Mary University of London, London, UK.

Background: The National Institute for Health and Care Excellence (NICE) recommend that men on androgen deprivation therapy (ADT) for prostate cancer should receive supervised exercise to manage the side-effects of treatment. However, these recommendations are rarely implemented into practice. Community-based exercise professionals (CBEPs) represent an important target group to deliver the recommendations nationally, yet their standard training does not address the core competencies required to work with clinical populations, highlighting a need for further professional training. This paper describes the development of a training package to support CBEPs to deliver NICE recommendations.

Methods: Development of the intervention was guided by the Medical Research Council guidance for complex interventions and the Behaviour Change Wheel. In step one, target behaviours, together with their barriers and facilitators were identified from a literature review and focus groups with CBEPs (n = 22) and men on androgen deprivation therapy (n = 26). Focus group outputs were mapped onto the Theoretical Domains Framework (TDF) to identify theoretical constructs for change. In step two, behaviour change techniques and their mode of delivery were selected based on psychological theories and evidence to inform intervention content. In step three, the intervention was refined following delivery and subsequent feedback from intervention recipients and stakeholders.

Results: Six modifiable CBEPs target behaviours were identified to support the delivery of the NICE recommendations. Nine domains of the TDF were identified as key determinants of change, including: improving knowledge and skills and changing beliefs about consequences. To target the domains, we included 20 BCTs across 8 training modules and took a blended learning approach to accommodate different learning styles and preferences. Following test delivery to 11 CBEPs and feedback from 28 stakeholders, the training package was refined.

Conclusion: Established intervention development approaches provided a structured and transparent guide to intervention development. A training package for CBEPs was developed and should increase trust amongst patients and health care professionals when implementing exercise into prostate cancer care. Furthermore, if proven effective, the development and approach taken may provide a blueprint for replication in other clinical populations where exercise has proven efficacy but is insufficiently implemented.
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http://dx.doi.org/10.1186/s12913-021-06275-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982309PMC
March 2021

Macrophages Mediate the Antitumor Effects of the Oncolytic Virus HSV1716 in Mammary Tumors.

Mol Cancer Ther 2021 03 9;20(3):589-601. Epub 2020 Dec 9.

Department of Oncology and Metabolism, University of Sheffield Medical School, Sheffield, United Kingdom.

Oncolytic viruses (OV) have been shown to activate the antitumor functions of specific immune cells like T cells. Here, we show OV can also reprogram tumor-associated macrophage (TAM) to a less immunosuppressive phenotype. Syngeneic, immunocompetent mouse models of primary breast cancer were established using PyMT-TS1, 4T1, and E0771 cell lines, and a metastatic model of breast cancer was established using the 4T1 cell line. Tumor growth and overall survival was assessed following intravenous administration of the OV, HSV1716 (a modified herpes simplex virus). Infiltration and function of various immune effector cells was assessed by NanoString, flow cytometry of dispersed tumors, and immunofluorescence analysis of tumor sections. HSV1716 administration led to marked tumor shrinkage in primary mammary tumors and a decrease in metastases. This was associated with a significant increase in the recruitment/activation of cytotoxic T cells, a reduction in the presence of regulatory T cells and the reprograming of TAMs towards a pro-inflammatory, less immunosuppressive phenotype. These findings were supported by data demonstrating that human monocyte-derived macrophages host HSV1716 replication, and that this led to immunogenic macrophage lysis. These events were dependent on macrophage expression of proliferating cell nuclear antigen (PCNA). Finally, the antitumor effect of OV was markedly diminished when TAMs were depleted using clodronate liposomes. Together, our results show that TAMs play an essential role in support of the tumoricidal effect of the OV, HSV1716-they both host viral replication via a novel, PCNA-dependent mechanism and are reprogramed to express a less immunosuppressive phenotype.
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http://dx.doi.org/10.1158/1535-7163.MCT-20-0748DOI Listing
March 2021

Adjuvant Sorafenib for Renal Cell Carcinoma at Intermediate or High Risk of Relapse: Results From the SORCE Randomized Phase III Intergroup Trial.

J Clin Oncol 2020 12 14;38(34):4064-4075. Epub 2020 Oct 14.

Medical Research Council Clinical Trials Unit at University College London (UCL), Institute of Clinical Trials and Methodology, London, United Kingdom.

Purpose: SORCE is an international, randomized, double-blind, three-arm trial of sorafenib after surgical excision of primary renal cell carcinoma (RCC) found to be at intermediate or high risk of recurrence.

Patients And Methods: We randomly assigned participants (2:3:3) to 3 years of placebo (arm A), 1 year of sorafenib followed by 2 years of placebo (arm B), or 3 years of sorafenib (arm C). The initial sorafenib dose was 400 mg twice per day orally, amended to 400 mg daily. The primary outcome analysis, which was revised as a result of external results, was investigator-reported disease-free survival (DFS) comparing 3 years of sorafenib versus placebo.

Results: Between July 2007 and April 2013, we randomly assigned 1,711 participants (430, 642, and 639 participants in arms A, B, and C, respectively). Median age was 58 years, 71% of patients were men, 84% had clear cell histology, 53% were at intermediate risk of recurrence, and 47% were at high risk of recurrence. We observed no differences in DFS or overall survival in all randomly assigned patients, patients with high risk of recurrence, or patients with clear cell RCC only. Median DFS was not reached for 3 years of sorafenib or for placebo (hazard ratio, 1.01; 95% CI, 0.83 to 1.23; = .95). We observed nonproportional hazards; the restricted mean survival time (RMST) was 6.81 years for 3 years of sorafenib and 6.82 years for placebo (RMST difference, 0.01 year; 95% CI, -0.49 to 0.48 year; = .99). Despite offering treatment adaptations, more than half of participants stopped treatment by 12 months. Grade 3 hand-foot skin reaction was reported in 24% of participants on sorafenib.

Conclusion: Sorafenib should not be used as adjuvant therapy for RCC. Active surveillance remains the standard of care for patients at intermediate or high risk of recurrence after nephrectomy and is the appropriate control of our current international adjuvant RCC trial, RAMPART.
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http://dx.doi.org/10.1200/JCO.20.01800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768344PMC
December 2020

Guidance for the assessment and management of prostate cancer treatment-induced bone loss. A consensus position statement from an expert group.

J Bone Oncol 2020 Dec 2;25:100311. Epub 2020 Aug 2.

Academic Unit of Bone Metabolism, University of Sheffield, United Kingdom.

Context And Objective: Incidence of prostate cancer (PC) is increasing, but androgen deprivation therapy (ADT) and other therapies are substantially improving survival. In this context, careful consideration of skeletal health is required to reduce the risk of treatment-related fragility fractures and their associated morbidity and mortality. This risk is currently not well-managed. ADT causes significant loss of bone mineral density (BMD). In the metastatic setting, systemic treatments (e.g. chemotherapy, abiraterone, enzalutamide) are used alongside ADT and may require concomitant glucocorticoids. Both ADT and glucocorticoids pose significant challenges to skeletal health in a population of patients already likely to have ongoing age-related bone loss and/or comorbid conditions. Current PC guidelines lack specific recommendations for optimising bone health. This guidance presents evidence for assessment and management of bone health in this population, with specific recommendations for clinical practitioners in day-to-day PC management.

Methods: Structured meetings of key opinion leaders were integrated with a systematic literature review. Input and endorsement was sought from patients, nursing representatives and specialist societies.

Summary Of Guidance: All men starting or continuing long-term ADT should receive lifestyle advice regarding bone health. Calcium/vitamin D supplementation should be offered if required. Fracture risk should be calculated (using the FRAX® tool), with BMD assessment included where feasible. BMD should always be assessed where fracture risk calculated using FRAX® alone is close to the intervention threshold. Intervention should be provided if indicated by local or national guidelines e.g. UK National Osteoporosis Guideline Group (NOGG) thresholds. Men requiring bone protection therapy should be further assessed (e.g. renal function), with referral to specialist centres if available and offered appropriate treatment to reduce fracture risk. Those near to, but below an intervention threshold, and patients going on to additional systemic therapies (particularly those requiring glucocorticoids), should have FRAX® (including BMD) repeated after 12-18 months.

Patient Summary: Modern treatments for prostate cancer have led to significant improvements in survival and quality of life. However, some of these treatments may lead to weakening of patient's bones with risk of fracture and it is therefore important to monitor patients' bone health and provide bone protection where needed. This paper provides specific guidance to clinical teams, based on the most recent research evidence, to ensure optimal bone health in their patients.
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http://dx.doi.org/10.1016/j.jbo.2020.100311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7516275PMC
December 2020

The COMITS Model: A Framework for Successful Publishing.

J Contin Educ Nurs 2020 Oct;51(10):477-483

Publishing is a necessity for nursing faculty and a growing expectation for nurse clinicians. Overcoming personal, organizational, and publishing barriers to writing is critical for successful publishing. The purpose of this article is to introduce the COMITS model. COMITS is an acronym that represents the following concepts: Commitment, Organization, Mechanics, Interpersonal, Time, and Sustainability. Strategies for overcoming barriers are described. Using these strategies associated with the COMITS model provides a framework for overcoming barriers that often prevent nursing faculty and clinicians from publishing. [J Contin Educ Nurs. 2020;51(10):477-483.].
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http://dx.doi.org/10.3928/00220124-20200914-10DOI Listing
October 2020

Applying Design Thinking in Health Care: Reflections of Nursing Honors Program Students.

Creat Nurs 2020 Aug;26(3):169-174

Nursing faculty at the University of Alabama at Birmingham (UAB) incorporated design thinking (DT) into the curriculum of the UAB School of Nursing Honors Program as a framework for undergraduate students' immersion into research experiences. This article describes the experiences of students who participated in the first honors class that used DT and discusses how to incorporate DT into nursing research and quality improvement projects. Active learning strategies provided students various opportunities to conceptualize and apply the five-step DT process by identifying possible solutions to problems in clinical settings. Three major themes emerged from these reflections: trusting the process, cultivating empathy, and applying DT in the future. Students found that trusting the process of learning about DT facilitated their understanding of empathy's role in health care as they recognized DT's far-reaching applications beyond the honors program. A pragmatic, intuitive, and innovative approach to identifying problems and solutions, DT empowers nurses to creatively and confidently address issues they encounter to improve outcomes for their patients, health-care systems, and communities.
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http://dx.doi.org/10.1891/CRNR-D-19-00055DOI Listing
August 2020

Retropharyngeal abscess in a post-lung transplant cystic fibrosis patient with prior cervical fusion: a case study.

BMC Pulm Med 2020 Aug 24;20(1):224. Epub 2020 Aug 24.

University of Alabama at Birmingham School of Medicine, 1720 2nd Avenue South, FOT1155, Birmingham, AL, 35294-3412, USA.

Background: Cystic fibrosis (CF) is a chronic, genetic, incurable disease that affects primarily the respiratory and gastrointestinal systems. End-stage lung disease is the leading cause of death in people with CF, and lung transplant is required to preserve life. Anti-rejection medications are necessary post-transplant; however, these medications lower immune response and increase susceptibility to bacterial infections. Complications from infections post lung-transplant account for approximately 30% of CF-related deaths. Retropharyngeal abscess (RPA) is a rare deep neck infection that occurs most commonly in children. This is the case of a 45-year-old Caucasian male with CF who developed a retropharyngeal abscess post wisdom teeth extraction that seeded into hardware from a previous cervical disc fusion.

Case Presentation: The patient presented to the emergency department with severe neck and shoulder pain, limited range of motion in his arm and neck, and dysphonia. He reported feeling pain for 10 days and suspected the pain was caused by a weightlifting injury. The patient reported low-grade fever 5 days prior, which responded to acetaminophen. He was afebrile upon admission and in no respiratory distress. Diagnostic labs revealed WBC 22,000/uL and CRP 211 mg/L. The CT scan showed a large abscess in the retropharyngeal space between C2-C7. The immediate concern was airway obstruction and need for possible intubation or tracheostomy. The patient was transferred to ENT service with neurosurgery and transplant consults. The RPA was drained and lavaged. The cervical hardware was discovered to be infected and was removed. The source of the RPA infection was determined to be from the patient's wisdom teeth extraction 6 months prior to RPA. The patient received 8 weeks of intravenous ceftriaxone for Streptococcus pneumoniae bacteremia and underwent revision of his cervical fusion 3 months after hardware removal.

Conclusions: Clinicians should consider prophylactic antimicrobial therapy for immunocompromised patients when they are at increased risk for transient bacteremia such as following invasive procedures (e.g., tooth extraction). Prophylactic antimicrobial therapy could prevent potentially life-threatening infections such as RPA in immunocompromised patients.
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http://dx.doi.org/10.1186/s12890-020-01269-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446166PMC
August 2020

Personal Medicine and Bone Metastases: Biomarkers, Micro-RNAs and Bone Metastases.

Cancers (Basel) 2020 Jul 29;12(8). Epub 2020 Jul 29.

Department of Oncology and Metabolism, Weston Park Hospital, Whitham Road, Sheffield S10 2SJ, UK.

Bone metastasis is a major cause of morbidity within solid tumours of the breast, prostate, lung and kidney. Metastasis to the skeleton is associated with a wide range of complications including bone fractures, spinal cord compression, hypercalcaemia and increased bone pain. Improved treatments for bone metastasis, such as the use of anti-bone resorptive bisphosphonate agents, within post-menopausal women have improved disease-free survival; however, these treatments are not without side effects. There is thus a need for biomarkers, which will predict the risk of developing the spread to bone within these cancers. The application of molecular profiling techniques, together with animal model systems and engineered cell-lines has enabled the identification of a series of potential bone-metastasis biomarker molecules predictive of bone metastasis risk. Some of these biomarker candidates have been validated within patient-derived samples providing a step towards clinical utility. Recent developments in multiplex biomarker quantification now enable the simultaneous measurement of up to 96 micro-RNA/protein molecules in a spatially defined manner with single-cell resolution, thus enabling the characterisation of the key molecules active at the sites of pre-metastatic niche formation as well as tumour-stroma signalling. These technologies have considerable potential to inform biomarker discovery. Additionally, a potential future extension of these discoveries could also be the identification of novel drug targets within cancer spread to bone. This chapter summarises recent findings in biomarker discovery within the key bone metastatic cancers (breast, prostate, lung and renal cell carcinoma). Tissue-based and circulating blood-based biomarkers are discussed from the fields of genomics, epigenetic regulation (micro-RNAs) and protein/cell-signalling together with a discussion of the potential future development of these markers towards clinical development.
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http://dx.doi.org/10.3390/cancers12082109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465268PMC
July 2020

Two Unanticipated Pregnancies While on Cystic Fibrosis Gene-Specific Drug Therapy.

J Patient Exp 2020 Feb 26;7(1):4-7. Epub 2019 Nov 26.

School of Nursing, The University of Alabama at Birmingham, Birmingham, AL, USA.

Women with cystic fibrosis (CF) desire to become pregnant and accomplish the same life goals as women without CF. The underlying pathology of CF and medications used to treat this genetically transmitted disease can affect women's reproductive potential. An interview with Ana (pseudonym), who became pregnant twice while taking the medication lumacaftor/ivacaftor (LUMA/IVA), was analyzed using thematic analysis. She described her experiences related to "Fertility and Pregnancy Surrounding LUMA/IVA," the major theme that emerged from her narrative. While there are anecdotal reports of infants conceived by women on LUMA/IVA and other CF precision medications, pregnancy rates and outcomes are not systematically tracked. Education about risks and benefits of these medications should be provided as part of comprehensive clinical care.
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http://dx.doi.org/10.1177/2374373519826556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7036671PMC
February 2020

CApecitabine plus Radium-223 (Xofigo™) in breast cancer patients with BONe metastases (CARBON): study protocol for a phase IB/IIA randomised controlled trial.

Trials 2020 Jan 15;21(1):89. Epub 2020 Jan 15.

Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK.

Background: A substantial proportion of breast cancer patients develop metastatic disease, with over 450,000 deaths globally per year. Bone is the most common first site of metastatic disease accounting for 40% of all first recurrence and 70% of patients with advanced disease develop skeletal involvement. Treatment of bone metastases currently focusses on symptom relief and prevention and treatment of skeletal complications. However, there remains a need for further treatment options for patients with bone metastases. Combining systemic therapy with a bone-targeted agent, such as radium-223, may provide an effective treatment with minimal additional side effects.

Methods/design: CARBON is a UK-based, open-label, multi-centre study which comprises an initial safety phase to establish the feasibility and safety of combining radium-223 given on a 6-weekly schedule in combination with orally administered capecitabine followed by a randomised extension phase to further characterise the safety profile and provide preliminary estimation of efficacy.

Discussion: The CARBON study is important as the results will be the first to assess radium-223 with chemotherapy in advanced breast cancer. If the results find acceptable rates of toxicity with a decrease in bone turnover markers, further work will be necessary in a phase II/III setting to assess the efficacy and clinical benefit.

Trial Registration: ISRCTN, ISRCTN92755158, Registered on 17 February 2016.
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http://dx.doi.org/10.1186/s13063-019-3643-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6961242PMC
January 2020

Bone Health in Men with Prostate Cancer: Review Article.

Curr Osteoporos Rep 2019 12;17(6):527-537

Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.

Purpose Of Review: The improvement in prostate cancer survival over time, even in those with advanced disease, has led to an increasing recognition of the impact of prostate cancer and its treatment on bone health. Cancer treatment-induced bone loss (CTIBL) is a well-recognized entity but greater awareness of the risks associated with CTIBL and its treatment is required.

Recent Findings: The principal culprit in causing CTIBL is hormonal ablation induced by prostate cancer treatment, including several new agents which have been developed in recent years which significantly improve survival, but may cause CTIBL. This review discusses the impact of prostate cancer and its treatment on bone health, including published evidence on the underlying pathophysiology, assessment of bone health, and strategies for prevention and treatment. It is important to recognize the potential cumulative impact of systemic prostate cancer treatments on bone health.
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http://dx.doi.org/10.1007/s11914-019-00536-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944652PMC
December 2019

Dedicator of Cytokinesis 4: A Potential Prognostic and Predictive Biomarker Within the Metastatic Spread of Breast Cancer to Bone.

Cancer Inform 2019 26;18:1176935119866842. Epub 2019 Aug 26.

Department of Oncology & Metabolism, Academic Unit of Clinical Oncology, The University of Sheffield, Sheffield, UK.

Metastasis to bone occurs in over 70% of patients with advanced breast cancer resulting in skeletal complications, including pathological fractures, hypercalcaemia, and bone pain. Significant advances have been made in the treatment of bone metastases, including the use of antiresorptive drugs, such as bisphosphonates, as well as antibody-based therapies targeting key signalling intermediates within the process of cancer-mediated bone destruction. Despite these advances, treatment is not without side effects, including osteonecrosis of the jaw therefore biomarkers predictive of which patients are at high risk of developing bone spread are required to enable personalized medicine initiatives within this important disease area. We used proteomic analysis to compare the protein expression within (1) a parental triple negative human breast cancer cell line, (2) a fully bone homing cell line and (3) a lung homing cell line. The bone and lung homing cell-lines were derived by intra-cardiac injection of fluorescently labelled cells within immune-compromised mice. Proteomics identified Dedicator of Cytokinesis 4 as a biomarker predictive of bone spread, and this finding was further supported by the observation that high levels of Dedicator of Cytokinesis 4 within primary breast tumours were predictive of breast cancer spread to bone. Here, we provide an overview of this study and put the findings into context.
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http://dx.doi.org/10.1177/1176935119866842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712742PMC
August 2019

Fulvestrant Plus Vistusertib vs Fulvestrant Plus Everolimus vs Fulvestrant Alone for Women With Hormone Receptor-Positive Metastatic Breast Cancer: The MANTA Phase 2 Randomized Clinical Trial.

JAMA Oncol 2019 Nov;5(11):1556-1564

Barts Cancer Institute, Centre for Experimental Cancer Medicine, Queen Mary University of London, London, United Kingdom.

Importance: Randomized clinical trials have demonstrated a substantial benefit of adding everolimus to endocrine therapy. Everolimus inhibits the mammalian target of rapamycin complex 1 (mTORC1) complex but not mTORC2, which can set off an activating feedback loop via mTORC2. Vistusertib, a dual inhibitor of mTORC1 and mTORC2, has demonstrated broad activity in preclinical breast cancer models, showing superior activity to everolimus.

Objective: To evaluate the safety and efficacy of vistusertib in combination with fulvestrant compared with fulvestrant alone or fulvestrant plus everolimus in postmenopausal women with estrogen receptor-positive advanced or metastatic breast cancer.

Design, Setting, And Participants: The MANTA trial is an open-label, phase 2 randomized clinical trial in which 333 patients with estrogen receptor-positive breast cancer progressing after prior aromatase inhibitor treatment underwent randomization (2:3:3:2) between April 1, 2014, and October 24, 2016, at 88 sites in 9 countries: 67 patients were assigned to receive fulvestrant, 103 fulvestrant plus vistusertib daily, 98 fulvestrant plus vistusertib intermittently, and 65 fulvestrant plus everolimus. Treatment was continued until disease progression, development of unacceptable toxic effects, or withdrawal of consent. Analysis was performed on an intention-to-treat basis.

Interventions: Fulvestrant alone or in combination with vistusertib (continuous or intermittent dosing schedules) or everolimus.

Main Outcomes And Measures: The primary end point was progression-free survival (PFS).

Results: Among the 333 women in the study (median age, 63 years [range, 56-70 years]), median PFS was 5.4 months (95% CI, 3.5-9.2 months) with fulvestrant, 7.6 months (95% CI, 5.9-9.4 months) with fulvestrant plus daily vistusertib, 8.0 months (95% CI, 5.6-9.9 months) with fulvestrant plus intermittent vistusertib, and 12.3 months (95% CI, 7.7-15.7 months) with fulvestrant plus everolimus. There was no significant difference in PFS between those receiving fulvestrant plus daily or intermittent vistusertib and fulvestrant alone (hazard ratio, 0.88 [95% CI, 0.63-1.24]; P = .46; and hazard ratio, 0.79 [95% CI, 0.55-1.12]; P = .16).

Conclusions And Relevance: The combination of fulvestrant plus everolimus demonstrated significantly longer PFS compared with fulvestrant plus vistusertib or fulvestrant alone. The trial failed to demonstrate a benefit of adding the dual mTORC1 and mTORC2 inhibitor vistusertib to fulvestrant.

Trial Registration: ClinicalTrials.gov identifier: NCT02216786 and EudraCT number: 2013-002403-34.
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http://dx.doi.org/10.1001/jamaoncol.2019.2526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6865233PMC
November 2019

Tumour profiling tests to guide adjuvant chemotherapy decisions in early breast cancer: a systematic review and economic analysis.

Health Technol Assess 2019 06;23(30):1-328

Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.

Background: Breast cancer and its treatment can have an impact on health-related quality of life and survival. Tumour profiling tests aim to identify whether or not women need chemotherapy owing to their risk of relapse.

Objectives: To conduct a systematic review of the effectiveness and cost-effectiveness of the tumour profiling tests onco DX (Genomic Health, Inc., Redwood City, CA, USA), MammaPrint (Agendia, Inc., Amsterdam, the Netherlands), Prosigna (NanoString Technologies, Inc., Seattle, WA, USA), EndoPredict (Myriad Genetics Ltd, London, UK) and immunohistochemistry 4 (IHC4). To develop a health economic model to assess the cost-effectiveness of these tests compared with clinical tools to guide the use of adjuvant chemotherapy in early-stage breast cancer from the perspective of the NHS and Personal Social Services.

Design: A systematic review and health economic analysis were conducted.

Review Methods: The systematic review was partially an update of a 2013 review. Nine databases were searched in February 2017. The review included studies assessing clinical effectiveness in people with oestrogen receptor-positive, human epidermal growth factor receptor 2-negative, stage I or II cancer with zero to three positive lymph nodes. The economic analysis included a review of existing analyses and the development of a de novo model.

Results: A total of 153 studies were identified. Only one completed randomised controlled trial (RCT) using a tumour profiling test in clinical practice was identified: Microarray In Node-negative Disease may Avoid ChemoTherapy (MINDACT) for MammaPrint. Other studies suggest that all the tests can provide information on the risk of relapse; however, results were more varied in lymph node-positive (LN+) patients than in lymph node-negative (LN0) patients. There is limited and varying evidence that onco DX and MammaPrint can predict benefit from chemotherapy. The net change in the percentage of patients with a chemotherapy recommendation or decision pre/post test ranged from an increase of 1% to a decrease of 23% among UK studies and a decrease of 0% to 64% across European studies. The health economic analysis suggests that the incremental cost-effectiveness ratios for the tests versus current practice are broadly favourable for the following scenarios: (1) onco DX, for the LN0 subgroup with a Nottingham Prognostic Index (NPI) of > 3.4 and the one to three positive lymph nodes (LN1-3) subgroup (if a predictive benefit is assumed); (2) IHC4 plus clinical factors (IHC4+C), for all patient subgroups; (3) Prosigna, for the LN0 subgroup with a NPI of > 3.4 and the LN1-3 subgroup; (4) EndoPredict Clinical, for the LN1-3 subgroup only; and (5) MammaPrint, for no subgroups.

Limitations: There was only one completed RCT using a tumour profiling test in clinical practice. Except for onco DX in the LN0 group with a NPI score of > 3.4 (clinical intermediate risk), evidence surrounding pre- and post-test chemotherapy probabilities is subject to considerable uncertainty. There is uncertainty regarding whether or not onco DX and MammaPrint are predictive of chemotherapy benefit. The MammaPrint analysis uses a different data source to the other four tests. The Translational substudy of the Arimidex, Tamoxifen, Alone or in Combination (TransATAC) study (used in the economic modelling) has a number of limitations.

Conclusions: The review suggests that all the tests can provide prognostic information on the risk of relapse; results were more varied in LN+ patients than in LN0 patients. There is limited and varying evidence that onco DX and MammaPrint are predictive of chemotherapy benefit. Health economic analyses indicate that some tests may have a favourable cost-effectiveness profile for certain patient subgroups; all estimates are subject to uncertainty. More evidence is needed on the prediction of chemotherapy benefit, long-term impacts and changes in UK pre-/post-chemotherapy decisions.

Study Registration: This study is registered as PROSPERO CRD42017059561.

Funding: The National Institute for Health Research Health Technology Assessment programme.
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http://dx.doi.org/10.3310/hta23300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627008PMC
June 2019

Metastatic bone disease: Pathogenesis and therapeutic options: Up-date on bone metastasis management.

J Bone Oncol 2019 Apr 6;15:004-4. Epub 2018 Nov 6.

Medical Oncology Unit, Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, P.za Giulio Cesare, 11, 70124 Bari, Italy.

Bone metastases (BM) are a common complication of cancer, whose management often requires a multidisciplinary approach. Despite the recent therapeutic advances, patients with BM may still experience skeletal-related events and symptomatic skeletal events, with detrimental impact on quality of life and survival. A deeper knowledge of the mechanisms underlying the onset of lytic and sclerotic BM has been acquired in the last decades, leading to the development of bone-targeting agents (BTA), mainly represented by anti-resorptive drugs and bone-seeking radiopharmaceuticals. Recent pre-clinical and clinical studies have showed promising effects of novel agents, whose safety and efficacy need to be confirmed by prospective clinical trials. Among BTA, adjuvant bisphosphonates have also been shown to reduce the risk of BM in selected breast cancer patients, but failed to reduce the incidence of BM from lung and prostate cancer. Moreover, adjuvant denosumab did not improve BM free survival in patients with breast cancer, suggesting the need for further investigation to clarify BTA role in early-stage malignancies. The aim of this review is to describe BM pathogenesis and current treatment options in different clinical settings, as well as to explore the mechanism of action of novel potential therapeutic agents for which further investigation is needed.
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http://dx.doi.org/10.1016/j.jbo.2018.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6429006PMC
April 2019

Setting Research Priorities in Partnership with Patients to Provide Patient-centred Urological Cancer Care.

Eur Urol 2019 06 23;75(6):891-893. Epub 2019 Mar 23.

Department of Surgery, University of Cambridge, Addenbrooke's Hospital, Cambridge Biomedical Campus, Cambridge, UK. Electronic address:

There is a well-documented discrepancy in prioritisation of research agendas between patients and researchers. Patient involvement in urological research from the outset is critical for well-prioritised research.
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http://dx.doi.org/10.1016/j.eururo.2019.03.008DOI Listing
June 2019

Essential Research Priorities in Renal Cancer: A Modified Delphi Consensus Statement.

Eur Urol Focus 2020 09 14;6(5):991-998. Epub 2019 Feb 14.

Department of Surgery, University of Cambridge, Addenbrooke's Hospital, Cambridge Biomedical Campus, Cambridge, UK. Electronic address:

Background: Identification of clear and focused research priorities is crucial to drive research forward.

Objective: To identify research priorities in renal cell carcinoma (RCC) through a multidisciplinary collaboration between clinicians, researchers, and patients.

Design, Setting, And Participants: In phase I, 44 RCC experts provided 24 literature reviews within their field, summarising research gaps (RGs). Three expert discussion meetings and patient interviews were performed, and 39 potential RGs were identified. In phase II, experts (N=82) scored these gaps on a nine-point scale (1-3: not important; 4-6: important; 7-9: critical) through a multistep Delphi process involving three online surveys and two further consensus meetings. The surveys aimed to reach a consensus, defined as ≥70% agreement by experts.

Outcome Measurements And Statistical Analysis: Three iterations of the Delphi survey were performed. The results obtained after the third Delphi survey were distributed amongst the RCC experts and patient representatives for final feedback.

Results And Limitations: In the first Delphi survey, the response rate was 56% (46/82), increasing to 67% (55/82) and 71% (58/82) in the second and third iterations, respectively. Survey respondents included 45.7% urologists, 37.0% oncologists, 8.7% radiologists, and 8.6% other specialists (pathologists, health economists, geneticist, and scientists). The process resulted in the identification of 14 crucial RGs, across a broad range of RCC themes. Key themes included further research into systemic therapies for RCC and management strategies that maximise quality of life, especially in patient groups that are "difficult to treat" and have rarer RCC subtypes. Two crucial RGs relate to biomarkers and novel imaging approaches for both localised and metastatic disease, to enable prognostic risk stratification and individualise patient management. Study participants were from a UK and European setting; therefore, we acknowledge that the RGs identified represent European priorities.

Conclusions: These RGs will facilitate international collaboration towards a concerted attempt to improve patients' survival and quality of life.

Patient Summary: We formed a collaboration between researchers, clinicians, and patients to identify research priorities in kidney cancer. We identified 14 priorities that will improve patient outcomes by focusing on research efforts.
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http://dx.doi.org/10.1016/j.euf.2019.01.014DOI Listing
September 2020

Radiological Response Heterogeneity Is of Prognostic Significance in Metastatic Renal Cell Carcinoma Treated with Vascular Endothelial Growth Factor-targeted Therapy.

Eur Urol Focus 2020 09 6;6(5):999-1005. Epub 2019 Feb 6.

Barts Cancer Institute, CRUK Experimental Cancer Medicine Centre, London, UK; Department of Oncology, Royal Free NHS Foundation Trust, London, UK. Electronic address:

Background: Response evaluation criteria in solid tumours (RECIST) is widely used to assess tumour response but is limited by not considering disease site or radiological heterogeneity (RH).

Objective: To determine whether RH or disease site has prognostic significance in patients with metastatic clear-cell renal cell carcinoma (ccRCC).

Design, Setting, And Participants: A retrospective analysis was conducted of a second-line phase II study in patients with metastatic ccRCC (NCT00942877), evaluating 138 patients with 458 baseline lesions.

Intervention: The phase II trial assessed vascular endothelial growth factor-targeted therapy±Src inhibition.

Outcome Measurements And Statistical Analysis: RH at week 8 was assessed within individual patients with two or more lesions to predict overall survival (OS) using Kaplan-Meier method and Cox regression model. We defined a high heterogeneous response as occurring when one or more lesion underwent a ≥10% reduction and one or more lesion underwent a ≥10% increase in size. Disease progression was defined by RECIST 1.1 criteria.

Results And Limitations: In patients with a complete/partial response or stable disease by RECIST 1.1 and two or more lesions at week 8, those with a high heterogeneous response had a shorter OS compared to those with a homogeneous response (hazard ratio [HR] 2.01; 95% confidence interval [CI]: 1.39-2.92; p<0.001). Response by disease site at week 8 did not affect OS. At disease progression, one or more new lesion was associated with worse survival compared with >20% increase in sum of target lesion diameters only (HR 2.12; 95% CI: 1.43-3.14; p<0.001). Limitations include retrospective study design.

Conclusions: RH and the development of new lesions may predict survival in metastatic ccRCC. Further prospective studies are required.

Patient Summary: We looked at individual metastases in patients with kidney cancer and showed that a variable response to treatment and the appearance of new metastases may be associated with worse survival. Further studies are required to confirm these findings.
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http://dx.doi.org/10.1016/j.euf.2019.01.010DOI Listing
September 2020

Endogenous Production of IL1B by Breast Cancer Cells Drives Metastasis and Colonization of the Bone Microenvironment.

Clin Cancer Res 2019 05 22;25(9):2769-2782. Epub 2019 Jan 22.

Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom.

Purpose: Breast cancer bone metastases are incurable, highlighting the need for new therapeutic targets. After colonizing bone, breast cancer cells remain dormant, until signals from the microenvironment stimulate outgrowth into overt metastases. Here we show that endogenous production of IL1B by tumor cells drives metastasis and growth in bone.

Experimental Design: Tumor/stromal IL1B and IL1 receptor 1 (IL1R1) expression was assessed in patient samples and effects of the IL1R antagonist, Anakinra, or the IL1B antibody canakinumab on tumor growth and spontaneous metastasis were measured in a humanized mouse model of breast cancer bone metastasis. Effects of tumor cell-derived IL1B on bone colonization and parameters associated with metastasis were measured in MDA-MB-231, MCF7, and T47D cells transfected with /control.

Results: In tissue samples from >1,300 patients with stage II/III breast cancer, IL1B in tumor cells correlated with relapse in bone (HR = 1.85; 95% CI, 1.05-3.26; = 0.02) and other sites (HR = 2.09; 95% CI, 1.26-3.48; = 0.0016). In a humanized model of spontaneous breast cancer metastasis to bone, Anakinra or canakinumab reduced metastasis and reduced the number of tumor cells shed into the circulation. Production of IL1B by tumor cells promoted epithelial-to-mesenchymal transition (altered E-Cadherin, N-Cadherin, and G-Catenin), invasion, migration, and bone colonization. Contact between tumor and osteoblasts or bone marrow cells increased IL1B secretion from all three cell types. IL1B alone did not stimulate tumor cell proliferation. Instead, IL1B caused expansion of the bone metastatic niche leading to tumor proliferation.

Conclusions: Pharmacologic inhibition of IL1B has potential as a novel treatment for breast cancer metastasis.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-2202DOI Listing
May 2019

Novel mediators of breast cancer bone metastasis-insights from studies of gene-regulation and the global proteome.

Ann Transl Med 2018 Nov;6(Suppl 1):S71

Department of Oncology and Metabolism, The Medical School, Sheffield, UK.

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http://dx.doi.org/10.21037/atm.2018.10.41DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6291541PMC
November 2018

The Effect of a Perioperative Nursing Elective on Nursing Career Paths.

AORN J 2019 01;109(1):87-94

Nurse educators play a role in addressing the growing perioperative nurse shortage in the United States by implementing strategies to entice new graduates to this specialty. The purpose of our study was to determine if an undergraduate perioperative nursing elective influenced the career choices of nurses four to nine years after they graduated from a baccalaureate nursing program in the midwestern United States. Using a descriptive study design, 23 of 50 nurses responded to a survey about positions they have held since graduating and the influence of a perioperative nursing elective on their career choices. Twenty-six percent of nurses in this sample went on to work in the perioperative specialty, and the majority indicated they continued to consider perioperative nursing as a career choice. Considering the potential long-term effects of this strategy, incorporating a perioperative nursing elective into nursing school curricula could be helpful to address the shortage of perioperative nurses.
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http://dx.doi.org/10.1002/aorn.12444DOI Listing
January 2019

"If We Would Have Known": A Couple's Regret Over a Missed Opportunity to Have a Biological Child After Lung Transplantation.

J Patient Exp 2018 Dec 6;5(4):320-322. Epub 2018 Jun 6.

School of Nursing, The University of Alabama at Birmingham, Birmingham, AL, USA.

Cystic fibrosis (CF) is a genetic, chronic disease that results in thickened secretions in the respiratory, gastrointestinal, and reproductive tracts. Over 95% of males with CF have congenital bilateral absence of the vas deferens causing infertility. This is a case study of a 29-year-old male who underwent a lung transplant after 8 months of oxygen dependency secondary to poor lung function. Approximately 1 year posttransplant, he and his wife decided that they wanted to start a family and consulted a fertility specialist who advised them to utilize donor sperm due to the teratogenic effects of posttransplant medications. Taken by surprise with this news, they expressed regret about the missed opportunity for pretransplant sperm aspiration and cryopreservation to conceive a biological child. He reported, "If we would have known, we would have made sure I [banked] my own [sperm]." This case study highlights a critical gap in CF comprehensive clinical care.
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http://dx.doi.org/10.1177/2374373518778861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6295801PMC
December 2018

Identification and validation of DOCK4 as a potential biomarker for risk of bone metastasis development in patients with early breast cancer.

J Pathol 2019 03 25;247(3):381-391. Epub 2019 Jan 25.

Department of Oncology and Metabolism, Academic Unit of Clinical Oncology, University of Sheffield, Sheffield, UK.

Skeletal metastasis occurs in around 75% of advanced breast cancers, with the disease incurable once cancer cells disseminate to bone, but there remains an unmet need for biomarkers to identify patients at high risk of bone recurrence. This study aimed to identify such a biomarker and to assess its utility in predicting response to adjuvant zoledronic acid (zoledronate). We used quantitative proteomics (stable isotope labelling by amino acids in cell culture-mass spectrometry; SILAC-MS) to compare protein expression in a bone-homing variant (BM1) of the human breast cancer cell line MDA-MB-231 with parental non-bone-homing cells to identify novel biomarkers for risk of subsequent bone metastasis in early breast cancer. SILAC-MS showed that dedicator of cytokinesis protein 4 (DOCK4) was upregulated in bone-homing BM1 cells, confirmed by western blotting. BM1 cells also had enhanced invasive ability compared with parental cells, which could be reduced by DOCK4-shRNA. In a training tissue microarray (TMA) comprising 345 patients with early breast cancer, immunohistochemistry followed by Cox regression revealed that high DOCK4 expression correlated with histological grade (p = 0.004) but not oestrogen receptor status (p = 0.19) or lymph node involvement (p = 0.15). A clinical validation TMA used tissue samples and the clinical database from the large AZURE adjuvant study (n = 689). Adjusted Cox regression analyses showed that high DOCK4 expression in the control arm (no zoledronate) was significantly prognostic for first recurrence in bone (HR 2.13, 95%CI 1.06-4.30, p = 0.034). No corresponding association was found in patients who received zoledronate (HR 0.812, 95%CI 0.176-3.76, p = 0.790), suggesting that treatment with zoledronate may counteract the higher risk for bone relapse from high DOCK4-expressing tumours. High DOCK4 expression was not associated with metastasis to non-skeletal sites when these were assessed collectively. In conclusion, high DOCK4 in early breast cancer is significantly associated with aggressive disease and with future bone metastasis and is a potentially useful biomarker for subsequent bone metastasis risk. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.5197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6618075PMC
March 2019

Comprehensive geriatric assessment and decision-making in older men with incurable but manageable (chronic) cancer.

Support Care Cancer 2019 May 25;27(5):1755-1763. Epub 2018 Aug 25.

University of Sheffield, Sheffield, UK.

Purpose: In older cancer patients, treatment decision-making is often complex. A comprehensive geriatric assessment (CGA) is an established tool used in geriatric medicine to identify unmet need requiring intervention. This study aimed to assess whether using a CGA in older male cancer patients with incurable but manageable disease provides information that would alter a cancer clinician's intended management plan. Acceptability and feasibility were secondary aims.

Methods: Elderly men with incurable but manageable malignancies (advanced prostate cancer and multiple myeloma) who had previously received at least one line of treatment were recruited from hospital outpatient clinics. A CGA was undertaken. Additional parameters measuring pain, fatigue and disease-specific concerns were also recorded, at the recommendation of patient involvement groups. Results were made available to clinicians. Patient and clinician acceptability and changes in subsequent management were recorded.

Results: Forty-eight patients completed the study. The median ages were 70.8 years and 74 years for myeloma and prostate respectively. Most identified concerns are related to disease-specific concerns (93%), pain (91%), frailty (57%) and nutrition (52%). Results altered the clinician's oncological management plan in nine cases only. Patients found the format and content of CGA acceptable.

Conclusions: Many unmet needs were identified in this population of elderly men with manageable but non curable cancer which led to supportive care referrals and interventions. The CGA, however, did not result in significant changes in clinical oncology treatment plans for the majority of patients. The application of the CGA and other assessments was viewed positively by participants and can feasibly be undertaken in the outpatient oncology setting.
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http://dx.doi.org/10.1007/s00520-018-4410-zDOI Listing
May 2019
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