Outcomes from a mechanistic biomarker multi-arm and randomised study of liposomal MTP-PE (Mifamurtide) in metastatic and/or recurrent osteosarcoma (EuroSarc-Memos trial).

The phase III clinical study of adjuvant liposomal muramyl tripeptide (MTP-PE) in resected high-grade osteosarcoma (OS) documented positive results that have been translated into regulatory approval, supporting initial promise for innate immune therapies in OS. There remains, however, no new approved treatment such as MTP-PE for either metastatic or recurrent OS. Whilst the addition of different agents, including liposomal MTP-PE, to surgery for metastatic or recurrent high-grade osteosarcoma has tried to improve response rates, a mechanistic hiatus exists in terms of a detailed understanding the therapeutic strategies required in advanced disease. Here we report a Bayesian designed multi-arm, multi-centre, open-label phase II study with randomisation in patients with metastatic and/or recurrent OS, designed to investigate how patients with OS might respond to liposomal MTP-PE, either given alone or in combination with ifosfamide. Despite the trial closing because of poor recruitment within the allocated funding period, with no objective responses in eight patients, we report the design and feasibility outcomes for patients registered into the trial. We demonstrate the feasibility of the Bayesian design, European collaboration, tissue collection with genomic analysis and serum cytokine characterisation. Further mechanistic investigation of liposomal MTP-PE alone and in combination with other agents remains warranted in metastatic OS.

The emerging role of the lung microbiome and its importance in non-small cell lung cancer diagnosis and treatment.

Over the last 10 years, with the development of culture-free bacterial identification techniques, understanding of how the microbiome influences diseases has increased exponentially and has highlighted potential opportunities for its use as a diagnostic biomarker and interventional target in many diseases including malignancy. Initial research focused on the faecal microbiome since it contains the densest bacterial populations and many other mucosal sites, such as the lungs, were until recently thought to be sterile. However, in recent years, it has become clear that the lower airways are home to a dynamic bacterial population sustained by the migration and elimination of microbes from the gastrointestinal and upper airway tracts. As in the gut, the lung microbiome plays an important role in regulating mucosal immunity and maintaining the balance between immune tolerance and inflammation. Studies to date have all shown that the lung microbiome undergoes significant changes in the setting of pulmonary disease. In lung cancer, animal models and small patient cohort studies have suggested that microbiome dysbiosis may not only impact tumour progression and response to therapy, particularly immunotherapy, but also plays a key role in cancer pathogenesis by influencing early carcinogenic pathways. These early results have led to concerted efforts to identify microbiome signatures that represent diagnostic biomarkers of early-stage disease and to consider modulation of the lung microbiome as a potential therapeutic strategy. Lung microbiome research is in its infancy and studies to date have been small, single centre with significant methodological variation. Large, multicentre longitudinal studies are needed to establish the clinical potential of this exciting field.

Do ethnic patients report longer lung cancer intervals than Anglo-Australian patients?: Findings from a prospective, observational cohort study.

OBJECTIVE: Lung cancer patients from ethnic minorities have poorer outcomes than their Caucasian counterparts. We compared lung cancer intervals between culturally and linguistically diverse (CALD) and Anglo-Australian patients to identify ethnic disparities. METHODS: This was a prospective, observational cohort study comprising a patient survey and reviews of patients' hospital and general practice records. Across three states, 577 (407 Anglo-Australian and 170 CALD) patients were recruited and their hospital records reviewed. The survey was returned by 189 (135 Anglo-Australian and 54 CALD) patients, and a review was completed by general practitioners (GPs) of 99 (76 Anglo-Australian and 23 CALD) patients. Survival and Cox regression analyses were conducted. RESULTS: CALD patients had longer hospital diagnostic interval [median 30 days, 95% confidence interval (CI) 26-34] than Anglo-Australian patients (median 17, 95% CI 14-20), p = 0.005, hazard ratio (HR) = 1.32 (95% CI 1.09-1.60). This difference persisted after relevant factors were taken into consideration, adjusted HR = 1.26 (95% CI 1.03-1.54, p = 0.022). CALD patients also reported longer prehospital intervals; however, these differences were not statistically significant. CONCLUSION: Target interventions need to be developed to address ethnic disparity in hospital diagnostic interval.

Implementation of lung cancer multidisciplinary teams: a review of evidence-practice gaps.

Multidisciplinary care (MDC) is considered best practice in lung cancer care. Health care services have made significant investments in MDC through the establishment of multidisciplinary team (MDT) meetings. This investment is likely to be sustained in future. It is imperative that MDT meetings are efficient, effective, and sufficiently nimble to introduce new innovations to enable best practice. In this article, we consider the 'evidence-practice gaps' in the implementation of lung cancer MDC. These gaps were derived from the recurrent limitations outlined in existing studies and reviews. We address the contributions that implementation science and quality improvement can make to bridge these gaps by increasing translation and improving the uptake of innovations by teams.

Patients' experience of lung cancer care coordination: a quantitative exploration.

PURPOSE: Improving the coordination of care for people with lung cancer is a health priority. This study aimed to tailor an existing care coordination survey for a lung cancer population, investigate coordination experiences for patients who had received hospital-based treatment and identify any factors that may be associated with poor care coordination. METHODS: We conducted a cross-sectional survey of lung patients within two tertiary hospitals in Sydney, Australia. The Cancer Care Coordination Questionnaire for Patients (CCCQ-P) is a psychometrically valid and reliable survey originally developed for colorectal cancer. We pilot tested a survey adaptation with lung cancer patients, support group members and medical specialists (n = 49). A revised survey was mailed to eligible patients via their medical specialist. RESULTS: Fifty-three of 118 eligible participants (45%) completed the CCCQ-P; most had early-stage disease and were about 70 years old. Overall, participants reported positive experiences of care coordination (mean total score 78.1), with high scores on communication and navigation subscales. The most problematic areas related to administrative aspects of care coordination and communication and information provision. Two patient groups (those residing in regional and rural areas, or no experience with the health system prior to diagnosis) reported significantly lower scores on the navigation subscale. CONCLUSIONS: This study found that lung cancer patients' experience of care coordination was positive, but highlighted the need for strategies to assist patients living in rural areas, and those with no experience of the health care system. The CCCQ-P survey instrument can be used in future lung cancer studies.

The LEAD study protocol: a mixed-method cohort study evaluating the lung cancer diagnostic and pre-treatment pathways of patients from Culturally and Linguistically Diverse (CALD) backgrounds compared to patients from Anglo-Australian backgrounds.

BACKGROUND: Lung cancer is the leading cause of cancer mortality worldwide. Early diagnosis and treatment is a key factor in reducing mortality and improving patient outcomes. To achieve this, it is important to understand the diagnostic pathways of cancer patients. Patients from Culturally and Linguistically Diverse (CALD) are a vulnerable group for lung cancer with higher mortality rates than Caucasian patients. The aim of this study is to explore differences in the lung cancer diagnostic pathways between CALD and Anglo-Australian patients and factors underlying these differences. METHODS: This is a prospective, observational cohort study using a mixed-method approach. Quantitative data regarding time intervals in the lung cancer diagnostic pathways will be gathered via patient surveys, General practitioner (GP) review of general practice records, and case-note analysis of hospital records. Qualitative data will be gathered via structured interviews with lung cancer patients, GPs, and hospital specialists. The study will be conducted in five study sites across three states in Australia. Anglo-Australian patients and patients from five CALD groups (i.e., Arabic, Chinese, Greek, Italian and Vietnamese communities) will mainly be identified through the list of new cases presented at lung multidisciplinary team meetings. For the quantitative component, it is anticipated that 724 patients (362 Anglo-Australian and 362 CALD patients) will be recruited to obtain a final sample of 290 (145 per group) assuming a 50% patient survey completion rate and a 80% GP record review completion rate. For the qualitative component, 60 interviews with lung cancer patients (10 Anglo-Australian and 10 patients per CALD group), 20 interviews with GPs, and 20 interviews with specialists will be conducted. DISCUSSION: This is the first Australian study to compare the time intervals along the lung cancer diagnostic pathway between CALD and Anglo-Australian patients. The study will also explore the underlying patient, healthcare provider, and health system factors that influence the time intervals in the two groups. This information will improve our understanding of the effect of ethnicity on health outcomes among lung cancer patients and will inform future interventions aimed at early diagnosis and treatment for lung cancer, particularly patients from CALD backgrounds. TRIAL REGISTRATION: The project was retrospectively registered with Australian New Zealand Clinical Trials Registry (registration number: ACTRN12617000957392 , date registered: 4th July 2017).

Diagnosing Lung Cancer: The Complexities of Obtaining a Tissue Diagnosis in the Era of Minimally Invasive and Personalised Medicine.

The role of the respiratory physician in diagnosing lung cancer has increased in complexity over the last 20 years. Adenocarcinoma is now the prevailing histopathological sub-type of non-small cell lung cancer (NSCLC) resulting in more peripheral cancers. Conventional bronchoscopy is often not sufficient to obtain adequate tissue samples for diagnosis. Radiologically guided transthoracic biopsy is a sensitive alternative, but carries significant risks. These limitations have driven the development of complimentary bronchoscopic navigation techniques for peripheral tumour localisation and sampling. Furthermore, linear endobronchial ultrasound with transbronchial needle aspiration (EBUS-TBNA) is increasingly being chosen as the initial diagnostic procedure for those with central lesions and/or radiological evidence of node-positive disease. This technique can diagnose and stage patients in a single, minimally invasive procedure with a diagnostic yield equivalent to that of surgical mediastinoscopy. The success of molecular targeted therapies and immune checkpoint inhibitors in NSCLC has led to the increasing challenge of obtaining adequate specimens for accurate tumour subtyping through minimally invasive procedures. This review discusses the changing epidemiology and treatment landscape of lung cancer and explores the utility of current diagnostic options in obtaining a tissue diagnosis in this new era of precision medicine.

Implementation of a lung cancer multidisciplinary team standardised template for reporting to general practitioners: a mixed-method study.

OBJECTIVES: Few interventions have been designed that provide standardised information to primary care clinicians about the diagnostic and treatment recommendations resulting from cancer multidisciplinary team (MDT) (tumour board) meetings. This study aimed to develop, implement and evaluate a standardised template for lung cancer MDTs to provide clinical information and treatment recommendations to general practitioners (GPs). Specific objectives were to (1) evaluate template feasibility (acceptability, appropriateness and timeliness) with GPs and (2) document processes of preimplementation, implementation and evaluation within the MDT setting. DESIGN: A mixed-method study design using structured interviews with GPs and qualitative documentation of project logs about implementation processes. SETTING: Two hospitals in Central Sydney, New South Wales, Australia. PARTICIPANTS: 61 GPs evaluated the template. Two lung cancer MDTs, consisting of 33 clinicians, and eight researchers participated in template development and implementation strategy. RESULTS: The MDT-reporting template appears to be a feasible way of providing clinical information to GPs following patient presentation at a lung cancer MDT meeting. Ninety-five per cent of GPs strongly agreed or agreed that the standardised template provided useful and relevant information, that it was received in a timely manner (90%) and that the information was easy to interpret and communicate to the patient (84%). Implementation process data show that the investment made in the preimplementation stage to integrate the template into standard work practices was a critical factor in successful implementation. CONCLUSIONS: This study demonstrates that it is feasible to provide lung cancer MDT treatment recommendations to GPs through implementation of a standardised template. A simple intervention, such as a standardised template, can help to address quality gaps and ensure that timely information is communicated between tertiary and primary care healthcare providers.

A germline mutation of CDKN2A and a novel RPLP1-C19MC fusion detected in a rare melanotic neuroectodermal tumor of infancy: a case report.

BACKGROUND: Melanotic neuroectodermal tumor of infancy (MNTI) is exceptionally rare and occurs predominantly in the head and neck (92.8 % cases). The patient reported here is only the eighth case of MNTI presenting in an extremity, and the first reported in the fibula. CASE PRESENTATION: A 2-month-old female presented with a mass arising in the fibula. Exhaustive genomic, transcriptomic, epigenetic and pathological characterization was performed on the excised primary tumor and a derived cell line. Whole-exome analysis of genomic DNA from both the tumor and blood indicated no somatic, non-synonymous coding mutations within the tumor, but a heterozygous, unique germline, loss of function mutation in CDKN2A (p16(INK4A), D74A). SNP-array CGH on DNA samples revealed the tumor to be euploid, with no detectable gene copy number variants. Multiple chromosomal translocations were identified by RNA-Seq, and fusion genes included RPLP1-C19MC, potentially deregulating the C19MC cluster, an imprinted locus containing microRNA genes reactivated by gene fusion in embryonal tumors with multilayered rosettes. Since the presumed cell of origin of MNTI is from the neural crest, we also compared gene expression with a dataset from human neural crest cells and identified 185 genes with significantly different expression. Consistent with the melanotic phenotype of the tumor, elevated expression of tyrosinase was observed. Other highly expressed genes encoded muscle proteins and modulators of the extracellular matrix. A derived MNTI cell line was sensitive to inhibitors of lysine demethylase, but not to compounds targeting other epigenetic regulators. CONCLUSIONS: In the absence of somatic copy number variations or mutations, the fully transformed phenotype of the MNTI may have arisen in infancy because of the combined effects of a germline CDKN2A mutation, tumor promoting somatic fusion genes and epigenetic deregulation. Very little is known about the etiology of MNTI and this report advances knowledge of these rare tumors by providing the first comprehensive genomic, transcriptomic and epigenetic characterization of a case.

Protocol for the CHEST Australia Trial: a phase II randomised controlled trial of an intervention to reduce time-to-consult with symptoms of lung cancer.

INTRODUCTION: Lung cancer is the most common cancer worldwide, with 1.3 million new cases diagnosed every year. It has one of the lowest survival outcomes of any cancer because over two-thirds of patients are diagnosed when curative treatment is not possible. International research has focused on screening and community interventions to promote earlier presentation to a healthcare provider to improve early lung cancer detection. This paper describes the protocol for a phase II, multisite, randomised controlled trial, for patients at increased risk of lung cancer in the primary care setting, to facilitate early presentation with symptoms of lung cancer. METHODS/ANALYSIS: The intervention is based on a previous Scottish CHEST Trial that comprised of a primary-care nurse consultation to discuss and implement a self-help manual, followed by self-monitoring reminders to improve symptom appraisal and encourage help-seeking in patients at increased risk of lung cancer. We aim to recruit 550 patients from two Australian states: Western Australia and Victoria. Patients will be randomised to the Intervention (a health consultation involving a self-help manual, monthly prompts and spirometry) or Control (spirometry followed by usual care). Eligible participants are long-term smokers with at least 20 pack years, aged 55 and over, including ex-smokers if their cessation date was less than 15 years ago. The primary outcome is consultation rate for respiratory symptoms. ETHICS AND DISSEMINATION: Ethical approval has been obtained from The University of Western Australia's Human Research Ethics Committee (RA/4/1/6018) and The University of Melbourne Human Research Committee (1 441 433). A summary of the results will be disseminated to participants and we plan to publish the main trial outcomes in a single paper. Further publications are anticipated after further data analysis. Findings will be presented at national and international conferences from late 2016. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trial Registry ACTRN 1261300039 3752.

The effectiveness of lung cancer MDT and the role of respiratory physicians.

There is an increasing trend for the use of multi-disciplinary teams (MDT) in the management of complex medical conditions. The latter may include various cancers, including lung cancer. However, the use of MDT is not restricted to cancer management, but may include complex conditions like diabetes and other non-malignant disorders. There is an increasing trend to use MDT in the investigation and management of patients with suspected or proven lung cancer. This review examines the evidence that supports the efficacy, or otherwise, of lung cancer management in a MDT as opposed to individual care, who should be a member of a lung cancer MDT, and the specific role of the respiratory physician in a lung cancer MDT. Although it may seem to make common sense to manage lung cancer in a MDT setting, there is actually little in the way of high quality data to support this concept. The logistic and ethical difficulties in researching this issue are highlighted in this review.

Igf2 pathway dependency of the Trp53 developmental and tumour phenotypes.

Insulin-like growth factor 2 (IGF2) and the transformation related protein 53 (Trp53) are potent regulators of cell growth and metabolism in development and cancer. In vitro evidence suggests several mechanistic pathway interactions. Here, we tested whether loss of function of p53 leads to IGF2 ligand pathway dependency in vivo. Developmental lethality occurred in p53 homozygote null mice that lacked the paternal expressed allele of imprinted Igf2. Further lethality due to post-natal lung haemorrhage occurred in female progeny with Igf2 paternal null allele only if derived from double heterozygote null fathers, and was associated with a specific gene expression signature. Conditional deletion of Igf2(fl/fl) attenuated the rapid tumour onset promoted by homozygous deletion of p53(fl/fl) . Accelerated carcinoma and sarcoma tumour formation in p53(+/-) females with bi-allelic Igf2 expression was associated with reductions in p53 loss of heterozygosity and apoptosis. Igf2 genetic dependency of the p53 null phenotype during development and tumour formation suggests that targeting the IGF2 pathway may be useful in the prevention and treatment of human tumours with a disrupted Trp53 pathway.

Pregnancy outcomes in the current era of cystic fibrosis care: a 15-year experience.

BACKGROUND: With improvement in clinical care and longer survival of patients with cystic fibrosis (CF), pregnancy has become commonplace. However, the impact of pregnancy on maternal health and fetal outcomes requires ongoing review. METHODS: A retrospective study of 20 pregnancies from 18 women with CF during the period 1995-2009 was performed. Changes in lung function, body mass index (BMI) and development of gestational diabetes were recorded. Fetal outcomes and maternal survival were examined, and the influence of pre-pregnancy parameters on outcomes was evaluated. RESULTS: Mean maternal age at pregnancy was 29±5 years with a mean pre-pregnancy forced expiratory volume in 1 s (FEV1) of 65.6±20.8% predicted. Eleven of 20 pregnancies had a pre-pregnancy FEV1 <60% predicted. During pregnancy, FEV1% predicted fell by 4.8% (CI 1.6-7.9), but recovered to baseline within 6 months post-partum. Mothers gained a mean weight of 7.6±3.2 kg, and gestational diabetes developed in 43% of women. All women delivered live births apart from one therapeutic abortion. Five infants were preterm, and two mature infants had low birth weight. Three mothers either died or required lung transplantation after pregnancy (range 2.5-8.0 years). FEV1 <60% predicted and BMI <20 kg/m(2) were significant predictors of fetal complications. CONCLUSION: Most women tolerated pregnancy well without major complications despite many having at least moderate lung function impairment. Pre-pregnancy FEV1 and BMI were important predictors of outcomes.

Chronic myeloid leukaemia as a model of disease evolution in human cancer.

Chronic myeloid leukaemia (CML) can be considered as a paradigm for neoplasias that evolve through a multi-step process. CML is also one of the best examples of a disease that can be targeted by molecular therapy; however, the success of new 'designer drugs' is largely restricted to the chronic phase of the disease. If not cured at this stage, CML invariably progresses and transforms into an acute-type leukaemia undergoing a 'blast crisis'. The causes of this transformation are still poorly understood. What mechanisms underlie this progression, and are they shared by other common cancers?

Primitive, quiescent and difficult to kill: the role of non-proliferating stem cells in chronic myeloid leukemia.

Recent studies have identified primitive, malignant stem cells which have entered the G0-phase of the cell cycle to become 'quiescent' and which are present, in small numbers, in all chronic myeloid leukaemia (CML) patients. These cells have attracted intense scrutiny because they are proving exceptionally refractory to attempts to kill them, in vitro, using imatinib mesylate, the current first-line therapy for CML, or conventional chemotherapeutic agents, such as cytosine arabinoside. This insensitivity, or resistance, to drug treatment is ominous and has important implications for the clinical management of CML, particularly with regard to relapse following an imatinib-induced remission. In this review, we consider the known properties of this cell population, including recent evidence which suggests that transcription of BCR-ABL occurs at an exceptionally high level in these cells despite them having only a single copy of the oncogene. We also discuss possible alternative, Bcr-Abl-independent, mechanisms for the insensitivity of these cells to agents which promote apoptosis, including the putative role of transporter proteins in causing abnormal drug influx or efflux.

Bcr-Abl expression levels determine the rate of development of resistance to imatinib mesylate in chronic myeloid leukemia.

Chronic myeloid leukemia (CML) starts with the acquisition of a BCR-ABL fusion gene in a single hematopoietic stem cell, but the time to progression is unpredictable. Although the tyrosine kinase inhibitor imatinib mesylate is highly effective in the treatment of CML, its continuous administration is associated with development of resistance, particularly in advanced phase or blast crisis. We investigate here whether a feature of disease progression (i.e., elevated expression of Bcr-Abl in CD34+ progenitor cells from CML patients in blast crisis) has any bearing on the kinetics of resistance to imatinib. By studying cell lines that exogenously express Bcr-Abl over the range found from chronic phase to blast crisis of CML, we show that cells expressing high amounts of Bcr-Abl, as in blast crisis, are much less sensitive to imatinib and, more significantly, take a substantially shorter time for yielding a mutant subclone resistant to the inhibitor than cells with low expression levels, as in chronic phase. Our data suggest that the differential levels of the Bcr-Abl oncoprotein expressed by CD34+ CML cells may reflect the extent and duration of their response to imatinib; the relatively high levels of oncoprotein in advanced-phase disease may underlie the observed rapid development of resistance.

Dose-dependent effects of Bcr-Abl in cell line models of different stages of chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is caused by Bcr-Abl, an activated tyrosine kinase. The amounts of Bcr-Abl mRNA and protein in cells from patients in blast crisis (BC) are higher than in those chronic phase (CP), indicating that their expression rises with disease progression. In order to study this phenomenon on cells with the same genetic background, we transfected the 32D cell line with the BCR-ABL transgene and selected clones with graded expression of Bcr-Abl within the range found in cells from CP to BC. In vitro, we found that Bcr-Abl exerted dose-dependent effects upon growth factor dependence, clonogenicity and migration. However, the relationship between Bcr-Abl expression and cellular adhesion to fibronectin was more complex: rather than a direct positive correlation, clones that expressed low, but not high, levels of Bcr-Abl were less adhesive than growth factor stimulated, parental BCR-ABL-negative 32D cells. This finding parallels the situation with normal and CML-CP progenitors where the latter exhibit defective adhesion to fibronectin. Treatment with the tyrosine kinase inhibitor imatinib mesylate reversed the adhesion deficient phenotype of clones expressing low levels of Bcr-Abl. When injected subcutaneously into syngeneic mice, cell lines expressing high levels of Bcr-Abl rapidly induced tumors, whereas low-expressing clones led to tumor formation only after a prolonged latency. These findings suggest that the level of Bcr-Abl may be essential in determining the phenotype of the leukemic clone at different stages of the disease.