Nicole Wong

A specific requirement for PDGF-C in palate formation and PDGFR-alpha signaling

PDGF-C is a member of the platelet-derived growth factor (PDGF) family, which signals through PDGF receptor (PDGFR) αα and αβ dimers. Here we show that Pdgfc−/− mice die in the perinatal period owing to feeding and respiratory difficulties associated with a complete cleft of the secondary palate. This phenotype was less severe than that of Pdgfra−/− embryos. Pdgfc−/− Pdgfa−/− embryos developed a cleft face, subepidermal blistering, deficiency of renal cortex mesenchyme, spina bifida and skeletal and vascular defects. Complete loss of function of both ligands, therefore, phenocopied the loss of PDGFR-α function, suggesting that both PDGF-A and PDGF-C signal through PDGFR-α to regulate the development of craniofacial structures, the neural tube and mesodermal organs. Our results also show that PDGF-C signaling is a new pathway in palatogenesis, different from, and independent of, those previously implicated.

Sequential allocation and global pattern of movement of the definitive endoderm in the mouse embryo during gastrulation

During mouse gastrulation, endoderm cells of the dorsal foregut are recruited ahead of the ventral foregut and move to the anterior region of the embryo via different routes. Precursors of the anterior-most part of the foregut and those of the mid- and hind-gut are allocated to the endoderm of the mid-streak-stage embryo, whereas the precursors of the rest of the foregut are recruited at later stages of gastrulation. Loss of Mixl1 function results in reduced recruitment of the definitive endoderm, and causes cells in the endoderm to remain stationary during gastrulation. The observation that the endoderm cells are inherently unable to move despite the expansion of the mesoderm in the Mixl1-null mutant suggests that the movement of the endoderm and the mesoderm is driven independently of one another.

Twist is required for patterning the cranial nerves and maintaining the viability of mesodermal cells

Twist encodes a basic helix‐loop‐helix transcription factor that is required for normal craniofacial morphogenesis in the mouse. Loss of Twist activity in the cranial mesenchyme leads to aberrant migratory behaviour of the neural crest cells, whereas Twist‐deficient neural crest cells are located in an inappropriate location in the first branchial arch and display defective osteogenic and odontogenic differentiation (Soo et al. [ 2002 ] Dev. Biol. 247:251–270). Results of the present study further show that loss of Twist impacts on the patterning of the cranial ganglia and nerves but not that of the peripheral ganglia and nerves in the trunk region of the body axis. Analyses of the expression of molecular markers of early differentiation of the paraxial mesoderm and the histogenetic potency of somites of Twist‐/‐ embryos reveal that Twist‐deficient somites can differentiate into muscles, cartilage, and bones, albeit less prolifically. Twist function, therefore, is not essential for mesoderm differentiation. The poor growth of the Twist‐deficient somites after transplantation to the ectopic site may be attributed to reduced proliferative capacity and extensive apoptosis of the paraxial mesoderm, suggesting that Twist is required for maintaining cell proliferation and viability in the mesodermal progenitors. Developmental Dynamics 230:216–228, 2004.

Panitumumab added to docetaxel, cisplatin and fluoropyrimidine in oesophagogastric cancer: ATTAX3 phase II trial.

Background:This randomised phase II study evaluated the efficacy and safety of panitumumab added to docetaxel-based chemotherapy in advanced oesophagogastric cancer.Methods:Patients with metastatic or locally recurrent cancer of the oesophagus, oesophagogastric junction or stomach received docetaxel and a fluoropyrimidine with or without panitumumab for 8 cycles or until progression. The primary end point was response rate (RECIST1.1). We planned to enrol 100 patients, with 50% expected response rate for combination therapy.Results:A total of 77 patients were enrolled. A safety alert from the REAL3 trial prompted a review of data that found no evidence of adverse outcomes associated with panitumumab but questionable efficacy, and new enrolment was ceased. Enrolled patients were treated according to protocol. Response rates were 49% (95% CI 34–64%) in the chemotherapy arm and 58% (95% CI 42–72%) in the combination arm. Common grade 3 and 4 toxicities included infection, anorexia, vomiting, diarrhoea and fatigue. At 23.7 months of median follow-up, median progression-free survival was 6.9 months vs 6.0 months and median overall survival was 11.7 months vs 10.0 months in the chemotherapy arm and the combination arm, respectively.Conclusions:Adding panitumumab to docetaxel-based chemotherapy for advanced oesophagogastric cancer did not improve efficacy and increased toxicities.

Systematic Review of the Costs and Benefits of Prescribed Cannabis-Based Medicines for the Management of Chronic Illness: Lessons from Multiple Sclerosis

IntroductionCannabis-based medicines (CBMs) may offer relief from symptoms of disease; however, their additional cost needs to be considered alongside their effectiveness. We sought to review the economic costs and benefits of prescribed CBMs in any chronic illness, and the frameworks used for their economic evaluation.MethodsA systematic review of eight medical and economic databases, from inception to mid-December 2016, was undertaken. MeSH headings and text words relating to economic costs and benefits, and CBMs were combined. Study quality was assessed using relevant checklists and results were synthesised in narrative form.ResultsOf 2514 identified records, ten studies met the eligibility criteria, all for the management of multiple sclerosis (MS). Six contained economic evaluations, four studies reported utility-based quality of life, and one was a willingness-to-pay study. Four of five industry-sponsored cost–utility analyses for MS spasticity reported nabiximols as being cost-effective from a European health system perspective. Incremental cost-effectiveness ratios per quality-adjusted life-year (QALY) gained for these five studies were £49,257 (UK); £10,891 (Wales); €11,214 (Germany); €4968 (Italy); and dominant (Spain). Nabiximols for the management of MS spasticity was not associated with statistically significant improvements in EQ-5D scores compared with standard care. Study quality was moderate overall, with limited inclusion of both relevant societal costs and discussions of potential bias.ConclusionsPrescribed CBMs are a potentially cost-effective add-on treatment for MS spasticity; however, this evidence is uncertain. Further investment in randomised trials with in-built economic evaluations is warranted for a wider range of clinical indications.Systematic review registrationPROSPERO Registration Number: CRD42014006370.

Long-term outcomes of accelerated BEP (bleomycin, etoposide, cisplatin) for advanced germ cell tumours: updated analysis of an Australian multicentre phase II trial by the Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP).

Germ cell tumours such as testicular cancer typically affect adolescent and young adult males. Since the introduction of cisplatin, outcomes for patients with advanced germ cell tumours have improved with cure rates exceeding 80% overall. However, outcomes are considerably worse for patients with intermediate or poor prognostic features with cure rates of only 79% and 48%, respectively [1]. We previously reported a single-arm, multicentre, open-label, phase II trial (Australian New Zealand Clinical Trials Registry: ACTRN12607000294459) of 43 patients with metastatic germ cell tumours [2]. They were treated using an accelerated regimen of first-line bleomycin, etoposide, and cisplatin (BEP) chemotherapy by cycling 2-weekly rather than the standard of 3-weekly cycles. The primary end point of feasibility was met, with 86% of patients able to complete the etoposide and cisplatin components of BEP and be eligible to receive a fourth cycle of BEP by day 50, i.e. with a delay of no more than 7 days. Efficacy appeared promising. We now present long-term efficacy outcomes after over 5 years of median follow-up. Eligibility and study procedures have been described in detail in the main study report [2]. In brief, patients were eligible if they had metastatic germ cell tumours arising in the testis, retroperitoneum, mediastinum, or ovary of any International Germ Cell Cancer Collaborative Group (IGCCCG) prognostic group and if they had radiologically measurable disease. Patients received cisplatin 20 mg/m on days 1, 2, 3, 4, 5; etoposide 100 mg/m on days 1, 2, 3, 4, 5; and pegylated G-CSF 6 mg on day 6, all repeated every 2 weeks for four cycles (or three cycles for good-risk patients). Bleomycin was given at 30 kIU weekly to a total 12 doses (9 doses for good risk). Forty-three eligible patents were enrolled between February 2008 and November 2010. According to the IGCCCG prognostic group, 12 had poor-risk disease, 16 intermediate-risk disease, and 15 good-risk disease. With a data cut-off date of 1 November 2015, the median follow-up was 6.2 years (inter-quartile range: 5.7–6.5) for survival and 6.2 years (inter-quartile range: 5.7–6.4) for relapse. Eight of 43 patients relapsed; 2 relapses occurred within 3 months of enrolment (refractory disease), 6 relapses occurred between 3 and 15 months (early relapse), and no late relapses occurred. Three of 43 patients died. All had experienced disease relapse; however, one patient had a complete response to second-line treatment and died due to an unrelated malignancy (secondary to Li Fraumeni syndrome). The 5-year progressionfree survival was 50% [95% confidence interval (CI) 21% to 74%] for poor-prognosis, 94% (95% CI 65% to 99%) for intermediateprognosis, and 93% (95% CI 61% to 99%) for good-prognosis patients. The 5-year overall survival was 92% (95% CI 54% to 99%) for poor-prognosis, 94% (95% CI 63% to 99%) for intermediate-prognosis, and 100% (95% CI NA) for good-prognosis patients. In summary, the long-term efficacy data of accelerated BEP in this phase II trial remain promising. This trial and a similar UK study [3] provide the rationale for a currently recruiting Australian-led international randomised phase III trial comparing accelerated versus standard BEP chemotherapy (Australian New Zealand Clinical Trials Registry: ACTRN12613000496718).

721PA MULTI-CENTRE, PHASE II, OPEN-LABEL, SINGLE ARM STUDY OF PANITUMUMAB, CISPLATIN AND GEMCITABINE IN BILIARY TRACT CANCER: PRIMARY RESULTS OF THE AGITG TACTIC STUDY

ABSTRACT Aim: Curative surgery is possible in less than a third of patients with biliary tract carcinoma (BTC). Most patients die of progressive cancer. This trial was designed to combine an optimal schedule of gemcitabine and cisplatin with the EGFR antibody panitumumab in patients with BTC. The primary objective was to determine the clinical benefit of this combination in KRAS wild-type (WT) BTC. Methods: Patients with KRAS WT locally advanced or metastatic BTC received gemcitabine1000mg/m2, cisplatin 25mg/m2 IV on days 1 and 8 of a 21 day cycle, with panitumumab 9mg/kg IV on day 1. KRAS status was determined by high resolution melt analysis PCR and confirmed with direct sequencing. The primary endpoint was objective clinical benefit at 12 weeks. The regimen was considered to be of interest if at least a 70% clinical benefit rate was achieved. Secondary endpoints included RR by RECIST v1.1; Time to treatment failure; Tolerability and safety; PFS; OS; Duration of response; CA19.9 response; QoL. Results: 80 patients were screened, 68 were WT KRAS (85%). Of these, 48 were enrolled between 2012 and 2013, across 14 Australian centres. Baseline demographics were well balanced with mean age 62yrs (range 40-82yrs). WHO PS 0 to 1. Most common grade III/IV adverse events were neutropenia (33.3%), infection (22.9%), thrombocytopenia (20%) and anaemia (16%). In addition, acneiform rash (12.5%), hypomagnesaemia (10.4%), fatigue (10.4%), vomiting (8.3%) and diarrhoea (6.3%) were also reported. The objective clinical benefit rate at 12 weeks was 84.1% (95% CI 69.5 – 92.1%); 18 SD (40%), 16 PR (36%) and 1 CR (2%). At this early assessment the actuarial rate of progression free survival is 8.4 months (95% CI 5.6 – 16.6%). Among 45 assessable patients, 20 (44%) were responders according to RECIST criteria (95% CI 31 – 59%). Data relating to the Secondary Endpoints will be presented at the meeting. Conclusions: The data presented confirms that the primary endpoint of the study was met. The combination of gemcitabine, cisplatin and panitumumab is a tolerable regimen with proven activity in our patient population. Further investigation of EGFR blockade in BTC is warranted. Disclosure: All authors have declared no conflicts of interest.

Oral cannabinoid-rich THC/CBD cannabis extract for secondary prevention of chemotherapy-induced nausea and vomiting: a study protocol for a pilot and definitive randomised double-blind placebo-controlled trial (CannabisCINV)

Introduction Chemotherapy-induced nausea and vomiting (CINV) remains an important issue for patients receiving chemotherapy despite guideline-consistent antiemetic therapy. Trials using delta-9-tetrahydrocannabinol-rich (THC) products demonstrate limited antiemetic effect, significant adverse events and flawed study design. Trials using cannabidiol-rich (CBD) products demonstrate improved efficacy and psychological adverse event profile. No definitive trials have been conducted to support the use of cannabinoids for this indication, nor has the potential economic impact of incorporating such regimens into the Australian healthcare system been established. CannabisCINV aims to assess the efficacy, safety and cost-effectiveness of adding TN-TC11M, an oral THC/CBD extract to guideline-consistent antiemetics in the secondary prevention of CINV. Methods and analysis The current multicentre, 1:1 randomised cross-over, placebo-controlled pilot study will recruit 80 adult patients with any malignancy, experiencing CINV during moderate to highly emetogenic chemotherapy despite guideline-consistent antiemetics. Patients receive oral TN-TC11M (THC 2.5mg/CBD 2.5 mg) capsules or placebo capsules three times a day on day −1 to day 5 of cycle A of chemotherapy, followed by the alternative drug regimen during cycle B of chemotherapy and the preferred drug regimen during cycle C. The primary endpoint is the proportion of subjects attaining a complete response to CINV. Secondary and tertiary endpoints include regimen tolerability, impact on quality of life and health system resource use. The primary assessment tool is patient diaries, which are filled from day −1 to day 5. A subsequent randomised placebo-controlled parallel phase III trial will recruit a further 250 patients. Ethics and dissemination The protocol was approved by ethics review committees for all participating sites. Results will be disseminated in peer-reviewed journals and at scientific conferences. Drug supply Tilray. Protocol version 2.0, 9 June 2017. Trial registration number ANZCTR12616001036404; Pre-results.