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Background and Aims: Lurbinectedin is a novel oncogenic transcription inhibitor active in several cancers, including small cell lung cancer (SCLC). We aimed to describe the first Australian experience of the clinical efficacy and tolerability of lurbinectedin for the treatment of SCLC after progression on platinum-containing therapy. Methods: Multicentre real-world study of individuals with SCLC initiating lurbinectedin monotherapy (3.2 mg/m2 three-weekly) on an early access programme between May 2020 and December 2021. Key outcomes were clinical utilisation, efficacy and tolerability. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan–Meier method. Outcome data were collected within the AUstralian Registry and biObank of thoRacic cAncers (AURORA). Results: Data were analysed for 46 individuals across seven sites. Lurbinectedin was given as second- (83%, 38/46) or subsequent- (17%, 8/46) line therapy, mostly with prior chemoimmunotherapy (87%, 40/46). We report dose modifications (17%, 8/46), interruptions/delays (24%, 11/46), high-grade toxicities (28%, 13/46) and hospitalisations (54%, 25/46) during active treatment. The overall response rate was 33% and the disease control rate was 50%. Six-month OS was 44% (95% confidence interval (CI): 29.0–57.1). Twelve-month OS was 15% (95% CI: 6.5–26.8). From lurbinectedin first dose, the median PFS was 2.5 months (95% CI: 1.8–2.9) and OS was 4.5 months (95% CI: 3.5–7.2). From SCLC diagnosis, the median OS was 12.9 months (95% CI: 11.0–17.2). Individuals with a longer chemotherapy-free interval prior to lurbinectedin had longer PFS and OS. Conclusion: This real-world national experience of lurbinectedin post-platinum chemotherapy and immunotherapy for individuals with SCLC was similar to that reported in clinical trials.

Objectives: To review the outcomes of immune checkpoint inhibitor (ICI) treatment of advanced cutaneous squamous cell carcinoma (CSCC) outside clinical trials. Study design: Retrospective observational study; review of patient records in fifteen Australian institutions. Setting, participants: All Australian adults with locally advanced or metastatic CSCC not amenable to curative surgery or radiotherapy treated with ICIs, 5 May 2017 – 23 May 2022, through a cemiplimab compassionate access scheme (Therapeutic Goods Administration Special Access Scheme) or who personally covered the cost of pembrolizumab prior to the start of the access scheme. Main outcome measures: Best overall response rate (ORR) according to standardised assessment criteria using the hierarchy: Response Evaluation Criteria in Solid Tumors (RECIST 1.1), the modified World Health Organization clinical response criteria, and the Positron Emission Tomography Response Criteria (PERCIST 1.0); overall and progression-free survival. Results: A total of 286 people with advanced CSCC received ICI therapy during May 2017 – May 2022 (cemiplimab, 270; pembrolizumab, 16). Their median age was 75.2 years (range, 39.3–97.5 years) and 232 were men (81%); median follow-up time was 12.2 months (interquartile range, 5.5–20.5 months). Eighty-eight people (31%) were immunocompromised, 27 had autoimmune disease, and 59 of 277 (21%) had ECOG performance scores of 2 or 3. The ORR was 60% (166 of 278 evaluable patients): complete responses were recorded for 74 (27%) and partial responses for 92 patients (33%). Twelve-month overall survival was 78% (95% confidence interval [CI], 72–83%); progression-free survival was 65% (95% CI, 58–70%). Poorer ECOG performance status was associated with poorer overall survival (per unit: adjusted hazard ratio [aHR], 3.0; 95% CI, 2.0–4.3) and progression-free survival (aHR, 2.4; 95% CI, 1.8–3.3), as was being immunocompromised (overall: aHR, 1.8; 95% CI, 1.1–3.0; progression-free: aHR, 1.8

BACKGROUND: Horizon scanning (HS) is the systematic identification of emerging therapies to inform policy and decision-makers. We developed an agile and tailored HS methodology that combined multi-criteria decision analysis weighting and Delphi rounds. As secondary objectives, we aimed to identify new medicines in melanoma, non-small cell lung cancer and colorectal cancer most likely to impact the Australian government's pharmaceutical budget by 2025 and to compare clinician and consumer priorities in cancer medicine reimbursement.METHOD: Three cancer-specific clinician panels (total n = 27) and a consumer panel (n = 7) were formed. Six prioritisation criteria were developed with consumer input. Criteria weightings were elicited using the Analytic Hierarchy Process (AHP). Candidate medicines were identified and filtered from a primary database and validated against secondary and tertiary sources. Clinician panels participated in a three-round Delphi survey to identify and score the top five medicines in each cancer type.RESULTS: The AHP and Delphi process was completed in eight weeks. Prioritisation criteria focused on toxicity, quality of life (QoL), cost savings, strength of evidence, survival, and unmet need. In both curative and non-curative settings, consumers prioritised toxicity and QoL over survival gains, whereas clinicians prioritised survival. HS results project the ongoing prevalence of high-cost medicines. Since completion in October 2021, the HS has identified 70 % of relevant medicines submitted for Pharmaceutical Benefit Advisory Committee assessment and 60% of the medicines that received a positive recommendation.CONCLUSION: Tested in the Australian context, our method appears to be an efficient and flexible approach to HS that can be tailored to address specific disease types by using elicited weights to prioritise according to incremental value from both a consumer and clinical perspective.POLICY SUMMARY: Since HS is

Introduction: Over the past decade, ALK tyrosine kinase inhibitors have delivered unprecedented survival for individuals with ALK-positive (ALK+) lung cancers. Real-world data enhance the understanding of optimal drug sequencing and expectations for survival. Methods: Multicenter real-world study of individuals with pretreated advanced ALK+ lung cancers managed on a lorlatinib access program between 2016 and 2020. Key outcomes were lorlatinib efficacy, tolerability, and treatment sequencing. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method among all individuals (PFSa and OSa), with at least 30 days (one-cycle) lorlatinib exposure (PFSb and OSb), and with good performance status (PFSc and OSc). Subgroups of interest were analyzed to assess signals of potential clinical applicability. Two OS index dates were analyzed, from lorlatinib initiation and advanced ALK+ diagnosis. Results: The population (N = 38, 10 sites) was heavily pretreated (23 had ≥ 2 previous treatment lines) with a high disease burden (26 had 2–4 sites and 11 had > 4 sites of metastatic disease, 19 had brain metastases). The overall response rate was 44% and the disease control rate was 81%. Lorlatinib dose reduction (18%), interruption (16%), and discontinuation (3%) were consistent with the trial experience. From advanced ALK+ diagnosis, the median OS for populations a, b, and c was 45.0 months, 69.9 months and 61.2 months respectively. From lorlatinib initiation, the median PFSa, PFSb and PFSc was 7.3 months, 13.2 months and 27.7 months and the median OSa, OSb and OSc was 19.9 months, 25.1 months and 27.7 months. The median PFSa with versus without brain metastases was 34.6 months versus 5.8 months (p = 0.09). The intracranial median PFS was 14.2 months. Previous good response versus poor response to the first ALK-directed therapy median PFSa was 27.7 months versus 4.7 months with a hazard ratio of 0.3 (p = 0.01). Conclusions: Lorlatinib is a p

Head and neck squamous cell carcinoma (HNSCC) represents a heterogeneous group of tumors. While significant progress has been made using multimodal treatment, the 5-year survival remains at 50%. Developing effective therapies, such as immunotherapy, will likely lead to better treatment of primary and metastatic disease. However, not all HNSCC tumors respond to immune checkpoint blockade therapy. Understanding the complex cellular composition and interactions of the tumor microenvironment is likely to lead to new knowledge for effective therapies and treatment resistance. In this review, we discuss HNSCC characteristics, predictive biomarkers, factors influencing immunotherapy response, with a focus on the tumor microenvironment.

Introduction: There is a strong theoretical rationale for combining checkpoint blockade with cytotoxic chemotherapy in pleural mesothelioma and other cancers. Two recent single-arm, phase 2 trials [DuRvalumab with chEmotherapy as first-line treAtment in advanced pleural Mesothelioma (DREAM) and Phase II multicenter study of anti-PD-L1, durvalumab, in combination with cisplatin and pemetrexed for the first-line treatment of unresectable malignant pleural mesothelioma (PrE0505)] combining the programmed death ligand-1 (PD-L1) inhibitor durvalumab with standard first-line chemotherapy exceeded prespecified safety and activity criteria to proceed to a phase 3 confirmatory trial to assess this combination. We present the protocol of the DREAM3R trial. Methods and analysis: This multicentre open-label randomised trial will recruit 480 treatment-naïve adults with advanced pleural mesothelioma, randomised (2:1) to either 3-weekly durvalumab 1500 mg plus 3-weekly doublet chemotherapy (cisplatin 75 mg/m 2 or carboplatin, Area Under the Curve,AUC 5 and pemetrexed 500 mg/m 2) 4-6 cycles, followed by 4-weekly durvalumab 1500 mg until disease progression, unacceptable toxicity or patient withdrawal; OR doublet chemotherapy alone for 4-6 cycles, followed by observation. The target accrual time is 27 months, with follow-up for an additional 24 months. This provides over 85% power if the true HR for overall survival (OS) is 0.70, with two-sided alpha of 0.05, assuming a median OS of 15 months in the control group. Randomisation is stratified by age (18-70 years vs >70), sex, histology (epithelioid vs non-epithelioid), platinum agent (cisplatin vs carboplatin) and region (USA vs Australia/New Zealand vs Other). The primary endpoint is OS. Secondary endpoints include progression-free survival, objective tumour response (by mRECIST V.1.1 and iRECIST), adverse events, health-related quality of life and healthcare resource use. Tertiary correlative objectives are to explore and valida

Head and neck squamous cell carcinoma (HNSCC) often presents with locoregional or distant disease, despite multimodal therapeutic approaches, which include surgical resection, chemoradiotherapy, and more recently, immunotherapy for metastatic or recurrent HNSCC. Therapies often target the primary and nodal regional HNSCC sites, and their efficacy at controlling occult distant sites remains poor. While our understanding of the tumor microenvironment conducive to effective therapies is increasing, the biology underpinning locoregional sites remains unclear. Here, we applied targeted spatial proteomic approaches to primary and lymph node metastasis from an oropharyngeal SCC (OPSCC) cohort to understand the expression of proteins within tumors, and stromal compartments of the respective sites in samples of both matched and unmatched patients. In unmatched analyses of n = 43 primary and 11 nodal metastases, our data indicated that tumor cells in nodal metastases had higher levels of Ki-67, PARP, BAD, and cleaved caspase 9, suggesting a role for increased proliferation, DNA repair, and apoptosis within these metastatic cells. Conversely, in matched analyses (n = 7), pro-apoptotic markers BIM and BAD were enriched in the stroma of primary tumors. Univariate, overall survival (OS) analysis indicated CD25 in tumor regions of primary tumors to be associated with reduced survival (HR = 3.3, p = 0.003), while progesterone receptor (PR) was associated with an improved OS (HR = 0.33, p = 0.015). This study highlights the utility of spatial proteomics for delineating the tumor and stromal compartment composition, and utility toward understanding these properties in locoregional metastasis. These findings indicate unique biological properties of lymph node metastases that may elucidate further understanding of distant metastatic in OPSCC.

Background: Lenvatinib is a multikinase inhibitor approved to treat radioiodine-refractory differentiated thyroid cancer (RR-DTC) at a starting dose of 24 mg/day. This study explored, in a double-blinded fashion, whether a starting dose of 18 mg/day would provide comparable efficacy with reduced toxicity. Methods: Patients with RR-DTC were randomized to lenvatinib 24 mg/day or 18 mg/day. The primary efficacy endpoint was objective response rate as of week 24 (ORRwk24); the odds ratio noninferiority margin was 0.4. The primary safety endpoint was frequency of grade ≥3 treatment-emergent adverse events (TEAEs) as of week 24. Tumors were assessed using RECIST v1.1. TEAEs were monitored and recorded. Results: The ORRwk24 was 57.3% (95% CI 46.1, 68.5) in the lenvatinib 24-mg arm and 40.3% (95% CI 29.3, 51.2) in the lenvatinib 18-mg arm, with an odds ratio (18/24 mg) of 0.50 (95% CI 0.26, 0.96). As of week 24, the rates of TEAEs grade ≥3 were 61.3% in the lenvatinib 24-mg arm and 57.1% in the lenvatinib 18-mg arm, a difference of -4.2% (95% CI -19.8, 11.4). Conclusion: A starting dose of lenvatinib 18 mg/day did not demonstrate noninferiority compared to a starting dose of 24 mg/day as assessed by ORRwk24 in patients with RR-DTC. The results represent a clinically meaningful difference in ORRwk24. The safety profile was comparable, with no clinically relevant difference between arms. These results support the continued use of the approved starting dose of lenvatinib 24 mg/day in patients with RR-DTC and adjusting the dose as necessary. Trial registration: ClinicalTrials.gov NCT02702388.

Objectives: Attaining tumour material from lung cancer patients can be challenging with limited sample availability. Therefore, non-invasive means of assessing tumour material is becoming increasingly more important. Circulating tumour DNA (ctDNA), extracted from a blood sample is appealing for the patient, and can be performed serially over the course of treatment. Materials and Methods: Here, we describe an approach for profiling the blood samples of 103 NSCLC patients for 73 variants in ctDNA across a panel of actionable lung cancer mutations using the UltraSEEK lung Panel (Agena Biosciences). Results: Our cross-sectional study showed tumour and blood concordance in the detection of KRAS mutations (G12C, G12D, G12A/V, G12R, G12RC, Q61H) in 17/27 (63%), EGFR mutations (e746_a750del, e747_A750, T790M, L861Q) in 16/20 (80%) with additional PIK3CA_p545K mutations across both cohorts. In patients without reported tumour mutations, 11/56 (19.6%) presented with plasma mutations across EGFR, KRAS and PIK3CA. Where ctDNA mutations were measured longitudinally (n = 4 patients), the individual mutations mirrored the response to therapy/progression of disease. Conclusion: Whilst preliminary, this study demonstrates the utility of detecting clinically actionable mutations in the blood samples of NSCLC patients at the time of presentation, and over the course of therapy.

Background: Immune checkpoint inhibitors (ICI) have shown durable and long-term benefits in a subset of head and neck squamous cell carcinoma (HNSCC) patients. To identify patient-responders from non-responders, biomarkers are needed which are predictive of outcome to ICI therapy. Cues in the tumor microenvironment (TME) have been informative in understanding the tumor-immune contexture. Methods: In this preliminary study, the NanoString GeoMx™ Digital Spatial Profiling (DSP) technology was used to determine the immune marker and compartment specific measurements in a cohort of HNSCC tumors from patients receiving ICI therapy. Results: Our data revealed that markers involved with immune cell infiltration (CD8 T-cells) were not predictive of outcome to ICI therapy. Rather, a number of immune cell types and protein markers (CD4, CD68, CD45, CD44, CD66b) were found to correlate with progressive disease. Cross platform comparison with the Opal Vectra (Perkin Elmer) for a number of markers across similar regions of interest demonstrated concordance for pan-cytokeratin, CD8, and PD-L1. Conclusion: This study, to our knowledge, represents the first digital spatial analysis of HNSCC tumors. A larger cohort of HNSCC will be required to orthogonally validate the findings.

Stroke can adversely affect the coordination and judgement of drivers due to executive dysfunction, which is relatively common in the post-stroke population but often undetected. Quantitatively examining vehicle control performance in post-stroke driving becomes essential to inspect whether and where post-stroke older drivers are risky. To date, it is unclear as to which indicators, such as lane keeping or speed control, can differentiate the driving performance of post-stroke older drivers from that of normal (neurotypical) older drivers. By employing a case-control design using advanced vehicle movement tracking and analysis technology, this pilot study aimed to compare the variations in driving trajectory, lane keeping and speed control between the two groups of older drivers using spatial and statistical techniques. The results showed that the mean standard deviation of lane deviation (SDLD) in post-stroke participants was higher than that of normal participants in complex driving tasks (U-turn and left turn) but almost the same in simple driving tasks (straight line sections). No statistically significant differences were found in the speed control performance. The findings indicate that, although older drivers can still drive as they need to after a stroke, the decline in cognitive abilities still imposes a higher cognitive workload and more effort for post-stroke older drivers. Future studies can investigate post-stroke adults driving behaviour at more challenging driving scenarios or design driving intervention programs to improve their executive function in driving.

Background: Standard first line treatment for unresectable malignant pleural mesothelioma (MPM) is platinum-based chemotherapy with pemetrexed. Two recent, single-arm, phase 2 trials (DREAM1 and PrE05052) combining the PD-L1 inhibitor durvalumab and standard first line cisplatin and pemetrexed (CP) exceeded pre-specified criteria for proceeding to phase 3. DREAM3R aims to determine the effectiveness of adding durvalumab to first line CP chemotherapy in advanced MPM. Methods: Treatment-naïve patients with advanced MPM will be randomised (2:1) to EITHER durvalumab 1500 mg every 3 weeks plus doublet chemotherapy (cisplatin 75 mg/m2 and pemetrexed 500 mg/m2) every 3 weeks for 4-6 cycles, followed by durvalumab 1500 mg every 4 weeks until disease progression, unacceptable toxicity or patient withdrawal; OR doublet chemotherapy alone for 4-6 cycles, followed by observation. The target sample size is 480 patients (320 durvalumab, 160 control) recruited over 27 months, with follow up for an additional 24 months. This provides over 85% power if the true hazard ratio for overall survival is 0.70, with 2-sided alpha of 0.05, assuming a median survival of 15 months in the control group. Key inclusion criteria: MPM of any histological subtype; measurable disease as per RECIST 1.1 modified for mesothelioma (mRECIST 1.1) without prior radiotherapy to these sites; ECOG PS 0-1; and, adequate hematologic, renal, and liver function tests. Key exclusion criteria: prior systemic anticancer treatment for MPM; diagnosis based only on cytology or fine needle aspiration biopsy; contraindication to immunotherapy; and conditions requiring immunosuppressives or corticosteroids. Stratification: Age (18-70 years vs. > 70), sex, histology (epithelioid vs. non-epithelioid), and region (USA vs. ANZ). The primary endpoint is overall survival. Secondary endpoints include progression-free survival; objective tumour response (by mRECIST 1.1 and iRECIST); adverse events; health-related qua

Objective: Until recently, standard first-line treatment for advanced mesothelioma was platinum chemotherapy with pemetrexed. Two recent, single-arm, phase 2 trials (DREAM and PrE0505) combining durvalumab with platinum-pemetrexed chemotherapy exceeded pre-specified criteria. DREAM3R aims to determine the effectiveness of adding durvalumab to platinum chemotherapy in advanced mesothelioma. Methods: Treatment naïve patients with advanced mesothelioma will be randomised (2:1) to either (A) durvalumab 1500 mg 3-weekly, with chemotherapy (Cisplatin 75 mg/m2 or Carboplatin AUC5, and pemetrexed 500 mg/m2) 3-weekly for four to six cycles, followed by durvalumab 1500 mg 4-weekly until disease progression, unacceptable toxicity or patient withdrawal; or (B) chemotherapy alone for four to six cycles, followed by observation. Stratification: Age (18-70 years vs. > 70), gender, histology (epithelioid vs. non-epithelioid), platinum drugs (cisplatin vs carboplatin) and region (ANZ vs USA vs others). An amendment is undergoing to add upfront carboplatin AUC 5 as a platinum choice and as a stratification factor. Key inclusion criteria: MPM of all histologies, measurable disease per modified RECIST 1.1 (mRECIST 1.1) without prior radiotherapy to these sites, ECOG 0-1 and adequate bone marrow, kidney and liver function tests. The primary endpoint is overall survival. Secondary endpoints include progression-free survival; objective tumour response (by mRECIST 1.1 and iRECIST); adverse events; health-related quality of life; and healthcare resource use. Tertiary endpoints: Potential prognostic and/or predictive biomarkers: PD-L1 expression, tumour mutation burden and nuanced genomic characteristics, and HLA type in tissue and serial blood samples; validation of radiological measures of response and studies of possible radiomic biomarkers in mesothelioma. The target sample size is 480 patients recruited over 27 months, with follow up

Introduction Sars-CoV-2 is a novel coronavirus responsible for COVID-19 officially declared pandemic in March 2020. Health systems worldwide responded with swift changes to increase workflow capacity while protecting the vulnerable, including those with cancer. This led to unprecedented and rapid restructuring of health service provision. Published data from the 2003 SARS pandemic focuses on medical and nursing staff, overlooking other departmental employees such as administration officers or food service workers. Our protocol aims to document directives and adjustments communicated to staff in two cancer care departments and correlate this with measures of distress and perceived preparedness across the spectrum of all staff involved in cancer care. Methods and analysis We use a semiqualitative approach comprising weekly diarising of events and simultaneous staff surveys. Principal investigators will document changes at a metropolitan quaternary cancer centre and a regional cancer centre. Communications, directives and changes will be diarised in real time in four executional domains. Simultaneously, prospective voluntary self-administered online surveys will be conducted at regular intervals by staff. The survey assesses the perceived institutional preparedness and personal well-being, with a combination of Likert scaled and open response questions. A semiquantitative self-assessment of distress adapted from National Comprehensive Cancer Network distress thermometer is incorporated. Additionally, open-text personal reflections on themes including difficult decisions will be invited. Survey participants will be drawn from various work areas of the cancer care departments: administrative staff, health professionals, for example, allied health, ancillary workers, nursing and medical. Ethics and dissemination The study has been reviewed and approved by the Human Research Ethics Committee (LNR/2020/QRBW/62982). Published literature on domains of distress neglects cat

Standard curative treatment of early-stage non-small cell lung cancer (NSCLC) involves surgery in combination with postoperative (adjuvant) platinum-based chemotherapy where indicated. Preoperative (neoadjuvant) therapies offer certain theoretical benefits compared with adjuvant approaches, including the ability to assess on-treatment response, reduce the tumor bulk prior to surgery, and enhance tolerability in the preoperative setting. Indeed, the use of neoadjuvant therapies are well established in other cancers such as breast and rectal cancers to debulk the tumor and guide ongoing therapy, and neoadjuvant chemotherapy has similar efficacy but less toxicity in NSCLC. More recently, immune checkpoint inhibitors (ICI) targeting programmed death-1 (PD1)/PD1-ligand 1 (PD-L1) have transformed the treatment of advanced NSCLC; the unique mechanisms of action of ICI offer additional rationale for assessment in the neoadjuvant setting. Preclinical studies in mouse cancer models support the proof of concept of neoadjuvant ICI (NAICI) through improvement of T-cell effector function and long-term memory induction. Preliminary early-phase human trial data support the proposition that NAICI in NSCLC may provide an feasible and potentially efficacious future treatment strategy and large, randomized phase III trials are currently recruiting to assess this approach. However, outstanding issues include defining optimal treatment combinations which balance high efficacy with acceptable toxicity, validating biomarkers to aid in patient selection, and avoiding potential pitfalls such as missing a window for successful surgery, that is, choosing the right drugs, for the right patient, at the right time. Predictive biomarkers to direct selection of therapy are required, and the validation of major pathological response (MPR) as a surrogate for survival will be important in the uptake of the neoadjuvant approach.

Stroke can adversely affect the coordination and judgement of drivers due to executive dysfunction, which is relatively common in the post-stroke population but often undetected. Quantitatively examining vehicle control performance in post-stroke driving becomes essential to inspect whether and where post-stroke older drivers are risky. To date, it is unclear as to which indicators, such as lane keeping or speed control, can differentiate the driving performance of post-stroke older drivers from that of normal (neurotypical) older drivers. By employing a case-control design using advanced vehicle movement tracking and analysis technology, this pilot study aimed to compare the variations in driving trajectory, lane keeping and speed control between the two groups of older drivers using spatial and statistical techniques. The results showed that the mean standard deviation of lane deviation (SDLD) in post-stroke participants was higher than that of normal participants in complex driving tasks (U-turn and left turn) but almost the same in simple driving tasks (straight line sections). No statistically significant differences were found in the speed control performance. The findings indicate that, although older drivers can still drive as they need to after a stroke, the decline in cognitive abilities still imposes a higher cognitive workload and more effort for post-stroke older drivers. Future studies can investigate post-stroke adults driving behaviour at more challenging driving scenarios or design driving intervention programs to improve their executive function in driving.

Stroke can adversely affect the coordination and judgement of drivers due to executive dysfunction, which is relatively common in the post-stroke population but often undetected. Quantitatively examining vehicle control performance in post-stroke driving becomes essential to inspect whether and where post-stroke older drivers are risky. To date, it is unclear as to which indicators, such as lane keeping or speed control, can differentiate the driving performance of post-stroke older drivers from that of normal (neurotypical) older drivers. By employing a case-control design using advanced vehicle movement tracking and analysis technology, this pilot study aimed to compare the variations in driving trajectory, lane keeping and speed control between the two groups of older drivers using spatial and statistical techniques. The results showed that the mean standard deviation of lane deviation (SDLD) in post-stroke participants was higher than that of normal participants in complex driving tasks (U-turn and left turn) but almost the same in simple driving tasks (straight line sections). No statistically significant differences were found in the speed control performance. The findings indicate that, although older drivers can still drive as they need to after a stroke, the decline in cognitive abilities still imposes a higher cognitive workload and more effort for post-stroke older drivers. Future studies can investigate post-stroke adults driving behaviour at more challenging driving scenarios or design driving intervention programs to improve their executive function in driving.

Stroke can adversely affect the coordination and judgement of drivers due to executive dysfunction, which is relatively common in the post-stroke population but often undetected. Quantitatively examining vehicle control performance in post-stroke driving becomes essential to inspect whether and where post-stroke older drivers are risky. To date, it is unclear as to which indicators, such as lane keeping or speed control, can differentiate the driving performance of post-stroke older drivers from that of normal (neurotypical) older drivers. By employing a case-control design using advanced vehicle movement tracking and analysis technology, this pilot study aimed to compare the variations in driving trajectory, lane keeping and speed control between the two groups of older drivers using spatial and statistical techniques. The results showed that the mean standard deviation of lane deviation (SDLD) in post-stroke participants was higher than that of normal participants in complex driving tasks (U-turn and left turn) but almost the same in simple driving tasks (straight line sections). No statistically significant differences were found in the speed control performance. The findings indicate that, although older drivers can still drive as they need to after a stroke, the decline in cognitive abilities still imposes a higher cognitive workload and more effort for post-stroke older drivers. Future studies can investigate post-stroke adults driving behaviour at more challenging driving scenarios or design driving intervention programs to improve their executive function in driving.

Stroke can adversely affect the coordination and judgement of drivers due to executive dysfunction, which is relatively common in the post-stroke population but often undetected. Quantitatively examining vehicle control performance in post-stroke driving becomes essential to inspect whether and where post-stroke older drivers are risky. To date, it is unclear as to which indicators, such as lane keeping or speed control, can differentiate the driving performance of post-stroke older drivers from that of normal (neurotypical) older drivers. By employing a case-control design using advanced vehicle movement tracking and analysis technology, this pilot study aimed to compare the variations in driving trajectory, lane keeping and speed control between the two groups of older drivers using spatial and statistical techniques. The results showed that the mean standard deviation of lane deviation (SDLD) in post-stroke participants was higher than that of normal participants in complex driving tasks (U-turn and left turn) but almost the same in simple driving tasks (straight line sections). No statistically significant differences were found in the speed control performance. The findings indicate that, although older drivers can still drive as they need to after a stroke, the decline in cognitive abilities still imposes a higher cognitive workload and more effort for post-stroke older drivers. Future studies can investigate post-stroke adults driving behaviour at more challenging driving scenarios or design driving intervention programs to improve their executive function in driving.

Stroke can adversely affect the coordination and judgement of drivers due to executive dysfunction, which is relatively common in the post-stroke population but often undetected. Quantitatively examining vehicle control performance in post-stroke driving becomes essential to inspect whether and where post-stroke older drivers are risky. To date, it is unclear as to which indicators, such as lane keeping or speed control, can differentiate the driving performance of post-stroke older drivers from that of normal (neurotypical) older drivers. By employing a case-control design using advanced vehicle movement tracking and analysis technology, this pilot study aimed to compare the variations in driving trajectory, lane keeping and speed control between the two groups of older drivers using spatial and statistical techniques. The results showed that the mean standard deviation of lane deviation (SDLD) in post-stroke participants was higher than that of normal participants in complex driving tasks (U-turn and left turn) but almost the same in simple driving tasks (straight line sections). No statistically significant differences were found in the speed control performance. The findings indicate that, although older drivers can still drive as they need to after a stroke, the decline in cognitive abilities still imposes a higher cognitive workload and more effort for post-stroke older drivers. Future studies can investigate post-stroke adults' driving behaviour at more challenging driving scenarios or design driving intervention programs to improve their executive function in driving.

Stroke can adversely affect the coordination and judgement of drivers due to executive dysfunction, which is relatively common in the post-stroke population but often undetected. Quantitatively examining vehicle control performance in post-stroke driving becomes essential to inspect whether and where post-stroke older drivers are risky. To date, it is unclear as to which indicators, such as lane keeping or speed control, can differentiate the driving performance of post-stroke older drivers from that of normal (neurotypical) older drivers. By employing a case-control design using advanced vehicle movement tracking and analysis technology, this pilot study aimed to compare the variations in driving trajectory, lane keeping and speed control between the two groups of older drivers using spatial and statistical techniques. The results showed that the mean standard deviation of lane deviation (SDLD) in post-stroke participants was higher than that of normal participants in complex driving tasks (U-turn and left turn) but almost the same in simple driving tasks (straight line sections). No statistically significant differences were found in the speed control performance. The findings indicate that, although older drivers can still drive as they need to after a stroke, the decline in cognitive abilities still imposes a higher cognitive workload and more effort for post-stroke older drivers. Future studies can investigate post-stroke adults driving behaviour at more challenging driving scenarios or design driving intervention programs to improve their executive function in driving.

Current treatment guidelines for patients with locally advanced head and neck squamous cell carcinoma (HNSCC) recommend multimodal treatment, including chemoradiation therapy (CRT) or surgery followed by radiation, with or without chemotherapy. The immune checkpoint inhibitor pembrolizumab has previously demonstrated antitumor activity in recurrent and/or metastatic HNSCC in large Phase III trials. For patients with locally advanced disease, Phase Ib data on the use of pembrolizumab in combination with chemoradiation have shown the approach to be safe and feasible. We describe here the design and rationale for KEYNOTE-412, a randomized, double-blind, Phase III trial investigating pembrolizumab or placebo administered concurrently with CRT and as maintenance treatment in patients with locally advanced HNSCC. Clinical Trial Registration: NCT03040999 (ClinicalTrials.gov).

Given that oropharyngeal squamous cell carcinoma (OPSCC) have now surpassed cervical cancer as the most common human papillomavirus (HPV)-driven cancer, there is an interest in developing non-invasive predictive biomarkers to early detect HPV-driven OPSCC. In total, 665 cancer-free individuals were recruited from Queensland, Australia. Oral HPV16 DNA positivity in those individuals was determined by our in-house developed sensitive PCR method. Individuals with (n = 9) or without (n = 12) oral HPV16 infections at baseline were followed for a median duration of 24 mo. Individuals with persistent oral HPV16 infection (≥ 30 mo) were invited for clinical examination of their oral cavity and oropharynx by an otolaryngologist. Oral HPV16 DNA was detected in 12 out of 650 cancer-free individuals (1.8%; 95% confidence interval [CI]: 1.0-3.2). Of the 3 individuals with persistent oral HPV16 infection, the first individual showed no clinical evidence of pathology. The second individual was diagnosed with a 2 mm invasive squamous cell carcinoma (T1N0M0) positive for both p16INK4a expression and HPV16 DNA. The third individual was found to have a mildly dysplastic lesion in the tonsillar region that was negative for p16INK4a expression and HPV16 DNA and she continues to have HPV16 DNA in her saliva. Taken together, our data support the value of using an oral HPV16 DNA assay as a potential screening tool for the detection of microscopic HPV-driven OPSCC. Larger multicenter studies across various geographic regions recruiting populations at a higher risk of developing HPV-driven OPSCC are warranted to extend and confirm the results of the current investigation.

Metastasis in cancer patients is reflected by measurable levels of circulating tumor cells (CTCs) in the blood of cancer patients. CTCs represent cancer cells from the primary and metastatic sites, thereby providing a comprehensive representation of the tumor burden of an individual patient. Recent advancements have shown that PD-1/PD-L1 immune checkpoint therapies have durable responses in a number of solid tumor types. Our study was designed to use multiple CTC enrichment platforms for the capture of CTCs and novel culture formulations for the ex vivo expansion of CTCs. Head and Neck cancer (n=350) and lung cancer (n=150) patients were recruited to investigate the prognostic role of CTCs. In parallel, a subset of HNC tumors were profiled using the NanoString GeoMx Digital Spatial Profiling (DSP) technology using a 44-plex antibody cocktail. We evaluated multiple CTC isolation technologies (CellSearch, filtration, CD45 depletion, Spiral, Straight and novel microfluidic chip technology) using matched patient samples which showed that epitope-independent CTC isolation captured a greater proportion of CTCs. Molecular alterations present in the primary tissue were confirmed in the CTCs by 3D-DNA FISH (EGFR-amplification, ALK-translocations). In HNC, the presence of CTC clusters associated with the development of distant metastatic disease (P=0.0313). HNC CTC-positive patients had shorter progression free survival (Hazard ratio [HR]: 4.946; 95% [CI]:1.571-15.57; P=0.0063) and PD-L1-positive CTCs were found to be significantly associated with worse outcome ([HR]:5.159; 95% [CI]:1.011-26.33; P=0.0485). In a proof of principle study, we were able to demonstrate for the first time, short-term patient derived CTC cultures outside the patient's body and exome sequencing of CTCs cultures confirmed the presence of mutational signatures consistent with The Cancer Genome Atlas (TCGA). Spatial characterization of the tumor microenvironment revealed immune subsets predicti

Background: There is a strong unmet need to improve systemic therapy in mesothelioma. Chemotherapy with cisplatin and pemetrexed improves survival in malignant pleural mesothelioma, and immune checkpoint inhibitors are an emerging treatment in this disease. We aimed to evaluate the activity of durvalumab, an anti-PD-L1 antibody, given during and after first-line chemotherapy with cisplatin and pemetrexed in patients with advanced malignant pleural mesothelioma. Methods: DREAM was a multicentre, single-arm, open-label, phase 2 trial done in nine hospitals in Australia. Eligible patients were aged 18 years or older and had histologically confirmed malignant pleural mesothelioma considered unsuitable for cancer-directed surgery, an Eastern Cooperative Oncology Group performance status of 0 or 1, and measurable disease as per the modified Response Evaluation Criteria in Solid Tumors version 1.0 (mRECIST) for mesothelioma that was previously untreated with systemic therapy. All histological subtypes were eligible. The first six participants were treated for two cycles in a safety run-in. All participants received cisplatin 75 mg/m2, pemetrexed 500 mg/m2, and durvalumab 1125 mg intravenously on day 1 of a 3-weekly schedule for a maximum of six cycles. Change from cisplatin to carboplatin with an area under the curve of 5 was permitted. Durvalumab was continued for a maximum of 12 months. The primary endpoint was progression-free survival at 6 months, measured according to mRECIST for malignant pleural mesothelioma and analysed in the intention-to-treat population. Safety analyses included all participants who receive at least one dose of any study drug. This study is registered with the Australia New Zealand Clinical Trials Registry, ACTRN12616001170415. Findings: Between Dec 28, 2016, and Sept 27, 2017, 55 participants were enrolled. 54 patients were eligible and were followed up for a median of 28·2 months (IQR 26·5–30·2)

Oropharyngeal cancer (OPC) caused by human papillomavirus (HPV) is a rising global concern. Early lesions are small and are often located in difficult to access areas (such as the crypts of the tonsils or base of tongue). Unlike cervical cancer, there is no standard or routine screening program for HPV-driven OPC. HPV DNA from OPC tumors may shed directly into saliva, and this can be used as a biomarker for early diagnosis. In this study, we report the first-ever clinically occult OPC in an asymptomatic patient discovered through a saliva test. This case relied upon serial measurements of HPV-16 DNA in saliva, which fell to undetectable levels following low morbidity, curative treatment.

Background: Studies suggest that combining radiotherapy (RT) with programmed cell death protein 1 (PD-1) blockade may elicit a synergistic antitumor response. We aimed to assess whether prior or concurrent RT was associated with improved disease control in patients with metastatic non–small cell lung cancer (NSCLC) treated with nivolumab. Methods: We conducted a retrospective study of patients receiving nivolumab as second or subsequent line therapy for metastatic NSCLC. Patients were categorized into those who received any RT for NSCLC prior to or during nivolumab therapy, and those with no history of RT for NSCLC. Results: A total of 85 patients received nivolumab between July 2015 and December 2016 and were followed up for a median of 15 months. Sixty-five patients (76.4%) received RT prior to or during nivolumab and 20 patients (23.6%) received nivolumab alone. Baseline characteristics of age, performance status, histology, smoking status and previous therapy were similar between the two groups. Prior or concurrent RT was associated with a superior PFS, median 2.8 months with RT versus 1.3 months without RT (Hazard Ratio (HR) = 0.494; 95% Confidence Interval (CI), 0.279–0.873; P = 0.02). The median OS of the group receiving RT was 6.4 months versus 4.2 months for the no RT group (P = 0.20). RT was not associated with an increase in toxicity. Conclusion: RT prior to or concurrent with nivolumab for metastatic NSCLC was associated with a modest improvement in PFS over nivolumab alone with no evidence of increase in adverse effects. RT may potentiate the effect of anti–PD-1 immunotherapy in NSCLC.

Current treatment guidelines for patients with locally advanced head and neck squamous cell carcinoma (HNSCC) recommend multimodal treatment, including chemoradiation therapy (CRT) or surgery followed by radiation, with or without chemotherapy. The immune checkpoint inhibitor pembrolizumab has previously demonstrated antitumor activity in recurrent and/or metastatic HNSCC in large Phase III trials. For patients with locally advanced disease, Phase Ib data on the use of pembrolizumab in combination with chemoradiation have shown the approach to be safe and feasible. We describe here the design and rationale for KEYNOTE-412, a randomized, double-blind, Phase III trial investigating pembrolizumab or placebo administered concurrently with CRT and as maintenance treatment in patients with locally advanced HNSCC. Clinical Trial Registration: NCT03040999 (ClinicalTrials.gov).

Adenosine mediates immunosuppression within the tumor microenvironment through triggering adenosine 2A receptors (A2AR) on immune cells. To determine whether this pathway could be targeted as an immunotherapy, we performed a phase I clinical trial with a small-molecule A2AR antagonist. We find that this molecule can safely block adenosine signaling in vivo. In a cohort of 68 patients with renal cell cancer (RCC), we also observe clinical responses alone and in combination with an anti-PD-L1 antibody, including subjects who had progressed on PD-1/PD-L1 inhibitors. Durable clinical benefit is associated with increased recruitment of CD8+ T cells into the tumor. Treatment can also broaden the circulating T-cell repertoire. Clinical responses are associated with an adenosine-regulated gene-expression signature in pretreatment tumor biopsies. A2AR signaling, therefore, represents a targetable immune checkpoint distinct from PD-1/PD-L1 that restricts antitumor immunity. SIGNIFICANCE: This first-in-human study of an A2AR antagonist for cancer treatment establishes the safety and feasibility of targeting this pathway by demonstrating antitumor activity with single-agent and anti-PD-L1 combination therapy in patients with refractory RCC. Responding patients possess an adenosine-regulated gene-expression signature in pretreatment tumor biopsies.See related commentary by Sitkovsky, p. 16.This article is highlighted in the In This Issue feature, p. 1.

While road safety in the United States (U.S.) has been continually improving since the 1970s, there are indications that these improvements are becoming increasingly difficult to sustain. Strategic Highway Safety Plans (SHSPs) are prepared by States to guide road safety management, however assessing the appropriateness of these plans remains a significant challenge, especially for the future in which they are to be applied. This study developed a new methodology to assess SHSPs from the perspectives of comprehensive system-based safety management and relevant future issues that can be applied before SHSPs are implemented, thereby avoiding long periods after implementation before assessing the appropriateness of the plans. A rating scale was developed and applied to assess 48 U.S. SHSPs against two key criteria: 1. a comprehensive framework for road safety, and 2. the anticipated changing, difficult and unpredictable nature of future transport and its context. The analysis concluded that current SHSPs have good national oversight with several strengths but were weak in some areas of content and did not address future challenges. Improvements are suggested to strengthen the plans thoroughness by being consistent with systems theory and practice, as well as ways that these SHSPs can be more resilient to future circumstances. Implementing the recommendations in this paper provides the opportunity to adopt a system-based safety management practice that has been successful in other hazardous industries. Doing so is expected to most efficiently and effectively continue the recent improvements to road safety, which is likely to be increasingly difficult otherwise.

While road safety in the United States (U.S.) has been continually improving since the 1970s, there are indications that these improvements are becoming increasingly difficult to sustain. Strategic Highway Safety Plans (SHSPs) are prepared by States to guide road safety management, however assessing the appropriateness of these plans remains a significant challenge, especially for the future in which they are to be applied. This study developed a new methodology to assess SHSPs from the perspectives of comprehensive system-based safety management and relevant future issues that can be applied before SHSPs are implemented, thereby avoiding long periods after implementation before assessing the appropriateness of the plans. A rating scale was developed and applied to assess 48 U.S. SHSPs against two key criteria: 1. a comprehensive framework for road safety, and 2. the anticipated changing, difficult and unpredictable nature of future transport and its context. The analysis concluded that current SHSPs have good national oversight with several strengths but were weak in some areas of content and did not address future challenges. Improvements are suggested to strengthen the plans thoroughness by being consistent with systems theory and practice, as well as ways that these SHSPs can be more resilient to future circumstances. Implementing the recommendations in this paper provides the opportunity to adopt a system-based safety management practice that has been successful in other hazardous industries. Doing so is expected to most efficiently and effectively continue the recent improvements to road safety, which is likely to be increasingly difficult otherwise.

Introduction: Local and distant metastatic disease occurs in approximately half of head and neck squamous cell carcinoma (HNSCC) patients, representing an ongoing cause for treatment failure. Circulating tumor cells (CTCs) are transient cancer cells which have the capacity to metastasize to distant sites such as the lungs and liver in HNSCC. When metastatic disease is radiographically evident, the patient prognosis is often poor. Therefore, methodologies to assess micrometastatic disease are needed to (1) identify patients likely to develop metastatic disease and (2) treat and monitor these patients more aggressively. Whilst CTCs are well documented in other tumor streams such as breast, colorectal cancer and prostate cancers, the data and clinical utility in HNSCC remains limited. Areas covered: Here we summarize the recent advances of CTCs and applications in HNSCC. Expert opinion: CTC enumeration can be prognostic in HNSCC; further studies are warranted to investigate the role of CTC clusters in HNSCC; CTC culture (in vivo/ex vivo) may present a possibility to expand these rare cells to a critical mass for functional testing; PD-L1 expression of HNSCC CTCs may present a means by which to determine patients likely to respond to therapy; a HNSCC CTC-specific marker is warranted.

Purpose: A randomised controlled trial was conducted to evaluate the effectiveness of a nurse-delivered Head and Neck Cancer Survivor Self-Management Care Plan (HNCP) for patients who had completed treatment for head and neck cancer (HNC). Methods: Ten oncology nurses were trained to deliver the HNCP. The HNCP consisted of one face-to-face hour-long meeting in which the patient’s treatment was recorded, as were contact details of health professionals involved in their care and follow-up schedules. Patients were guided to nominate up to three goals for their future well-being and assisted to devise an action plan to achieve these. The HNCP was given to the patient and a copy was forwarded to their primary care physician. One hundred and nine patients were randomised after definitive curative intent treatment, 36 to HNCP, 36 to receive information about survivorship, and 37 to usual care. The primary outcome, analysed by intention-to-treat, was change in quality of life measured by the FACT-H&N from baseline to 6-month follow-up. Results: Quality of life of all groups decreased at 3 months but was close to baseline at 6 months. Compared with the usual care group, the only statistically significant mean difference at 6 months was for the information group on the physical well-being domain (mean difference 0.4, 95% − 1.8, 2.6, p < 0.05). Conclusions: A single-session nurse-delivered intervention is insufficient to improve the quality of life in HNC survivors compared with usual care. Provision of detailed written information about HNC survivorship is associated with improved physical well-being. Trial registration: ACTRN12613000542796.

While road safety in the United States (U.S.) has been continually improving since the 1970's, there are indications that these improvements are becoming increasingly difficult to sustain. Strategic Highway Safety Plans (SHSPs) are prepared by States to guide road safety management, however assessing the appropriateness of these plans remains a significant challenge, especially for the future in which they are to be applied. This study developed a new methodology to assess SHSPs from the perspectives of comprehensive system-based safety management and relevant future issues that can be applied before SHSPs are implemented, thereby avoiding long periods after implementation before assessing the appropriateness of the plans. A rating scale was developed and applied to assess 48 U.S. SHSPs against two key criteria: 1. a comprehensive framework for road safety, and 2. the anticipated changing, difficult and unpredictable nature of future transport and its context. The analysis concluded that current SHSPs have good national oversight with several strengths but were weak in some areas of content and did not address future challenges. Improvements are suggested to strengthen the plans' thoroughness by being consistent with systems theory and practice, as well as ways that these SHSPs can be more resilient to future circumstances. Implementing the recommendations in this paper provides the opportunity to adopt a system-based safety management practice that has been successful in other hazardous industries. Doing so is expected to most efficiently and effectively continue the recent improvements to road safety, which is likely to be increasingly difficult otherwise.

While road safety in the United States (U.S.) has been continually improving since the 1970's, there are indications that these improvements are becoming increasingly difficult to sustain. Strategic Highway Safety Plans (SHSPs) are prepared by States to guide road safety management, however assessing the appropriateness of these plans remains a significant challenge, especially for the future in which they are to be applied. This study developed a new methodology to assess SHSPs from the perspectives of comprehensive system-based safety management and relevant future issues that can be applied before SHSPs are implemented, thereby avoiding long periods after implementation before assessing the appropriateness of the plans. A rating scale was developed and applied to assess 48 U.S. SHSPs against two key criteria: 1. a comprehensive framework for road safety, and 2. the anticipated changing, difficult and unpredictable nature of future transport and its context. The analysis concluded that current SHSPs have good national oversight with several strengths but were weak in some areas of content and did not address future challenges. Improvements are suggested to strengthen the plans' thoroughness by being consistent with systems theory and practice, as well as ways that these SHSPs can be more resilient to future circumstances. Implementing the recommendations in this paper provides the opportunity to adopt a system-based safety management practice that has been successful in other hazardous industries. Doing so is expected to most efficiently and effectively continue the recent improvements to road safety, which is likely to be increasingly difficult otherwise.

While road safety in the United States (U.S.) has been continually improving since the 1970s, there are indications that these improvements are becoming increasingly difficult to sustain. Strategic Highway Safety Plans (SHSPs) are prepared by States to guide road safety management, however assessing the appropriateness of these plans remains a significant challenge, especially for the future in which they are to be applied. This study developed a new methodology to assess SHSPs from the perspectives of comprehensive system-based safety management and relevant future issues that can be applied before SHSPs are implemented, thereby avoiding long periods after implementation before assessing the appropriateness of the plans. A rating scale was developed and applied to assess 48 U.S. SHSPs against two key criteria: 1. a comprehensive framework for road safety, and 2. the anticipated changing, difficult and unpredictable nature of future transport and its context. The analysis concluded that current SHSPs have good national oversight with several strengths but were weak in some areas of content and did not address future challenges. Improvements are suggested to strengthen the plans thoroughness by being consistent with systems theory and practice, as well as ways that these SHSPs can be more resilient to future circumstances. Implementing the recommendations in this paper provides the opportunity to adopt a system-based safety management practice that has been successful in other hazardous industries. Doing so is expected to most efficiently and effectively continue the recent improvements to road safety, which is likely to be increasingly difficult otherwise.

While road safety in the United States (U.S.) has been continually improving since the 1970s, there are indications that these improvements are becoming increasingly difficult to sustain. Strategic Highway Safety Plans (SHSPs) are prepared by States to guide road safety management, however assessing the appropriateness of these plans remains a significant challenge, especially for the future in which they are to be applied. This study developed a new methodology to assess SHSPs from the perspectives of comprehensive system-based safety management and relevant future issues that can be applied before SHSPs are implemented, thereby avoiding long periods after implementation before assessing the appropriateness of the plans. A rating scale was developed and applied to assess 48 U.S. SHSPs against two key criteria: 1. a comprehensive framework for road safety, and 2. the anticipated changing, difficult and unpredictable nature of future transport and its context. The analysis concluded that current SHSPs have good national oversight with several strengths but were weak in some areas of content and did not address future challenges. Improvements are suggested to strengthen the plans thoroughness by being consistent with systems theory and practice, as well as ways that these SHSPs can be more resilient to future circumstances. Implementing the recommendations in this paper provides the opportunity to adopt a system-based safety management practice that has been successful in other hazardous industries. Doing so is expected to most efficiently and effectively continue the recent improvements to road safety, which is likely to be increasingly difficult otherwise.

While road safety in the United States (U.S.) has been continually improving since the 1970s, there are indications that these improvements are becoming increasingly difficult to sustain. Strategic Highway Safety Plans (SHSPs) are prepared by States to guide road safety management, however assessing the appropriateness of these plans remains a significant challenge, especially for the future in which they are to be applied. This study developed a new methodology to assess SHSPs from the perspectives of comprehensive system-based safety management and relevant future issues that can be applied before SHSPs are implemented, thereby avoiding long periods after implementation before assessing the appropriateness of the plans. A rating scale was developed and applied to assess 48 U.S. SHSPs against two key criteria: 1. a comprehensive framework for road safety, and 2. the anticipated changing, difficult and unpredictable nature of future transport and its context. The analysis concluded that current SHSPs have good national oversight with several strengths but were weak in some areas of content and did not address future challenges. Improvements are suggested to strengthen the plans thoroughness by being consistent with systems theory and practice, as well as ways that these SHSPs can be more resilient to future circumstances. Implementing the recommendations in this paper provides the opportunity to adopt a system-based safety management practice that has been successful in other hazardous industries. Doing so is expected to most efficiently and effectively continue the recent improvements to road safety, which is likely to be increasingly difficult otherwise.

While road safety in the United States (U.S.) has been continually improving since the 1970's, there are indications that these improvements are becoming increasingly difficult to sustain. Strategic Highway Safety Plans (SHSPs) are prepared by States to guide road safety management, however assessing the appropriateness of these plans remains a significant challenge, especially for the future in which they are to be applied. This study developed a new methodology to assess SHSPs from the perspectives of comprehensive system-based safety management and relevant future issues that can be applied before SHSPs are implemented, thereby avoiding long periods after implementation before assessing the appropriateness of the plans. A rating scale was developed and applied to assess 48 U.S. SHSPs against two key criteria: 1. a comprehensive framework for road safety, and 2. the anticipated changing, difficult and unpredictable nature of future transport and its context. The analysis concluded that current SHSPs have good national oversight with several strengths but were weak in some areas of content and did not address future challenges. Improvements are suggested to strengthen the plans' thoroughness by being consistent with systems theory and practice, as well as ways that these SHSPs can be more resilient to future circumstances. Implementing the recommendations in this paper provides the opportunity to adopt a system-based safety management practice that has been successful in other hazardous industries. Doing so is expected to most efficiently and effectively continue the recent improvements to road safety, which is likely to be increasingly difficult otherwise.

This research aims to investigate travel mode choices and behaviours of air passengers and community respondents in regional Western Australia. Multinomial logit and Nested logit models were used for the mode choice analysis based on Stated-Preference survey data. The results indicate that travel cost, journey time, service frequency and seat comfort played important roles in affecting travellers' mode choices. For business trips, air passengers are willing to pay more to reduce journey time and increase seat comfort and service frequency compared to community respondents. While for non-business trips, these differences were much smaller. The findings will provide some insights in understanding people's mode choice behaviours and therefore guide policy makers and airlines in developing policies and practice.

Background: Immune checkpoint inhibitors are routinely used in Non Small Cell Lung Cancer (NSCLC) patients following progression on first-line therapy. Immune-related Adverse Events (IrAEs) have been associated with the efficacy of PD-1 inhibitors in melanoma. The association between the development of IrAEs and efficacy of nivolumab remains unclear in NSCLC. Methods: We retrospectively collected data from patients who received nivolumab for advanced NSCLC on an Open Access Program across seven oncology institutions in Queensland, Australia, and analyzed whether there was an association between outcomes and the development of immune-related toxicity. Results: One hundred and ninety six patients were enrolled to this ethics committee approved audit – 77 females (39%) and 119 (61%) males; PS 0-1 (62%); PS 2-3 (38%); median age 67 (range 42-84). An objective response was recorded in 24% of patients; partial response (47/196) with one complete response, in addition 28% (55/196) had stable disease. The median overall survival was 9.2 months; 13.4 months in PS 0-1 patients and 4.2 months in PS 2-3 patients. At 1 year, the overall survival rate was 42%; 57% in patients with PS 0-1 and 18% in PS 2-3 patients. The presence of IrAEs of any grade occurred in 36% of patients and was associated with a longer median PFS of 5.9 months versus 2.3 months (P value < 0.01, 95% CI) in patients with no immune toxicity on Kaplan Meier analysis. The median OS of patients experiencing an IrAE was 24.3 months compared with 6.5 months without (P value < 0.01, 95% CI). A durable clinical benefit was observed in 72% of patients who developed at least one IrAE versus 37% in those without any immune mediated toxicity. Analysis of the prognostic relevance of routine histological, hematological and biochemical parameters is ongoing with a multivariate analysis planned. Conclusions: Nivolumab had clinically significant long-term benefits in the treatment of locally advanced and metastatic NSCLC wit

Australia has the second highest incidence and death rate from malignant pleural mesothelioma (MPM) worldwide, after the United Kingdom. DREAM is an open-label, single arm, multi-centre, phase II trial designed to determine the activity, safety and tolerability of durvalumab combined with first-line chemotherapy in MPM. ACTRN12616001170415. Key eligibility criteria included all histological subtypes of MPM planned for first-line cisplatin and pemetrexed, unsuitability for radical surgery, no prior radiotherapy to measurement sites, and ECOG performance status of 0-1. Response was assessed using the mRECIST (modified Response Evaluation Criteria in Solid Tumors for MPM). Patients received durvalumab (1125mg), cisplatin (75mg/m2) and pemetrexed (500 mg/m2) 3-weekly for a maximum of six cycles, followed by durvalumab alone (1125 mg 3-weekly) up to 12 months or until progression or unacceptable toxicity. The primary endpoint was progression-free survival at 6 months (PFS6). Between Dec 2016 and Sep 2017, 54 patients were recruited. The median age was 68 (42–82) with 82% male and 60% ECOG 0. Forty-five patients (82%) had epithelioid subtype MPM. 31/54 (57%) of patients met primary endpoint of PFS6 with a median PFS of 6.8 months (95% CI: 5.4–9.0), at a median follow up time of 12 months, successfully rejecting the null hypothesis. The objective response rate (ORR) was 48% using mRECIST and 50% using iRECIST. The median duration of response was 6.5 months. 36 patients experienced grade 3-5 adverse events. Of four deaths on study, none were considered related to durvalumab treatment. Seventeen patients had irAEs of any grade, including 8 with G3-5 irAEs. Overall survival is maturing and will be presented at the meeting. Combination durvalumab with first-line chemotherapy for unresectable MPM showed promising activity and acceptable tolerability, with expected immune toxicities. Further evaluation to compare with chemotherapy alone will be generated through a phase 3 random

Background: DREAM is an open-label, single arm, multi-centre, phase II trial with a safety run in designed to determine the activity, safety and tolerability of durvalumab combined with cisplatin and pemetrexed as first line therapy in malignant pleural mesothelioma (MPM). ANZ Clinical trial registry number: ACTRN12616001170415. Methods: Chemotherapy-naïve patients with MPM of all histological subtypes, planned for first-line cisplatin and pemetrexed who had not received prior radiotherapy and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 were eligible. Patients received durvalumab (1125mg), cisplatin (75mg/m2) and pemetrexed (500mg/m2) 3-weekly for a maximum of 6 cycles, followed by durvalumab alone (1125 mg 3-weekly) until progression or to 12 months total therapy. Primary endpoint was progression-free survival at 6 months (PFS6). The design provides >90% power if the true PFS6 rate is 65%, with 5% type I error using an expected PFS6 from standard treatment of 45%. Matching tissue and bloods were collected for translational research. Results: Between Dec 2016 to Sep 2017 54 participants were recruited. The median age was 68 (42-82) with 82% male and 60% ECOG 0. They received a median of 6 cycles of chemotherapy (range 1-6) and 7 of durvalumab (given with and without chemotherapy) (range 1-18). The 6-patient safety run in confirmed the tolerability of chemoimmunotherapy. In the first 31 evaluable patients (pre-specified primary interim analysis), PFS6 based on modified RECIST (mRECIST) for MPM was 71%. The objective response rate (ORR) was 61% using mRECIST and 53% using iRECIST. Thirty-one patients (57%) experienced adverse events (AEs) that were grade ≥3. Nineteen patients (35%) had immune-related (ir) AEs including 2 grade 3 irAEs. Conclusions: In MPM, adding durvalumab to first line treatment with cisplatin and pemetrexed had higher rates of PFS6 and ORR than expected for chemotherapy alone, with acceptable tolerability. The final r

© 2018 Elsevier Ltd The aviation industry in Western Australia (WA) plays a vital role in the economic and social development of the state. However, accurate forecasts for passenger movements are not available to policy makers due to lack of relevant air travel demand information. The objective of this study is to estimate the domestic air passenger seat numbers between airport-pairs based on online flight information in regional WA based on a gravity model using Poisson pseudo-maximum likelihood estimation (PPML). Particularly, we aim to investigate the impact of distance, airfare, catchment areas, population, tourism and mining sector on forecasting air passenger seat numbers in order to inform and guide policy making. This research collected appropriate data and produced valid models that represent air passenger seat numbers offered on regular public transport (RPT) air services in regional WA. The models consider both geographic and service-related variables, such as the catchment area of airports, population and number of tourists in the airport's catchment area. Two kinds of airport catchment areas are generated in this study, based on Thiessen polygon and two and half hours’ driving distance. The Thiessen polygon catchment areas cover the whole WA regions, while the 2.5 h's driving catchment area covers only 32 percent of the WA region. The size of the catchment area can affect the magnitude of factors, and therefore influence the modelling results. When deciding the catchment area for the study, it is important to take the spatial distribution of factors into considerations. For both Thiessen polygon and two and half hours’ driving distance catchment area, the model results illustrate that distance between airports, airfare of the flight, population of the origin airport's catchment area and the number of operating mine sites of the destination airport's catchment area are significantly correlated with domestic air travel seat capacity provided. Given the gu

This abstract is freely available on the conference website at (see link below)

Immune checkpoint inhibitors have recently emerged as an exciting new treatment paradigm across a broad spectrum of malignancies. This new class of agents also challenges oncologists with a unique set of immune-based toxicities. Early recognition and precise management of these toxicities can result in better outcomes, with minimization of toxicity and harm to the patient. This article provides a comprehensive review of immune-based toxicities caused by immune checkpoint inhibitors, including recommendations for their investigation and guidelines for specific management.

Background: Early phase trials of anti-programmed death 1 (PD-1) antibodies have demonstrated important responses in malignant mesothelioma (MM). Expression of the ligand, PD-L1, is a potential biomarker for PD-1 directed therapy use and is expressed in a significant proportion of MM. We present results for a cohort treated with PD-1 inhibitory antibodies and assessed for PD-L1 expression. Methods: Patients (pts) with unresectable pleural or peritoneal mm treated with anti-PD-1 antibodies were included. Data was collected retrospectively. Radiological response was assessed using RECIST 1.1. Overall survival (OS) and progression-free survival (PFS) were evaluated. PD-L1 expression was assessed with IHC clone E1L3N (Cell Signaling Technology). PD-L1 positivity was defined as membranous expression on tumour cells: > 5% for PD-L1+ and > 50% for PD-L1hi. Results: Forty-six pts were treated between July 2015 and January 2017. Median age was 66.5 years, ECOG PS was 0/1 in 3/46 (7%) and 35/46 (76%) respectively. Most were male (83%), and 43/46 (93%) had ≥1 prior therapy, with a median of 2 (range 0 - 5). The predominant histology was epithelioid (n = 32/46; 70%). Pembrolizumab was used in 45/46 and BGB-A317 (a PD-L1 antibody) in 1 pt. Of the 46 pts, the overall response rate (ORR) was 15% (7 PR) with 15/46 (33%) achieving stable disease, giving a DCR of 44%. Progression was seen in 24/46 (52%). Median OS for the entire cohort was 8.0 months (95% CI: 2.3 – 11.9). Median duration of response was not yet reached (range 1.5 -19.8). PD-L1 testing was performed in 14 samples, with PD-L1+ in 5 (36%) and PD-L1hi in 4 (29%). The ORR was 40% (2 PR, 3 SD) with PD-L1+, 50% (2 PR, 2 SD) with PD-L1hi and 22% (2/9 patients) with negative expression. PFS and OS were greater with both PD-L1+ (PFS HR: 0.26, 95% CI 0.05 – 1.32, p = 0.10) and PD-L1hi(PFS HR: 0.17, 95% CI 0.02 – 1.47, p = 0.11). PD-L1+ positivity remained a borderline predictor of improved survival on multivariate analysis (p =

Internationally, road fatalities and injury are a massive public health, social, economic and transport problem that road safety strategies are developed to counteract. This thesis aimed to investigate and improve the applicability, responsiveness, efficiency and effectiveness of these strategies. A comprehensive and coherent framework, comprising nine mutually interacting Components, with 75 subcomponents, that contribute to crashes, and ten generic Policy Tools, was developed. The framework is based on safety and system theory, principles and practice.