Background:Lapatinib is a dual inhibitor of epidermal growth factor receptor (EGFR) and human EGFR-2 (HER-2) tyrosine kinases. This study investigated the pharmacodynamic and clinical effects of lapatinib in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN).Methods:In total, 107 therapy-naive patients with locally advanced SCCHN were randomised (2 : 1) to receive lapatinib or placebo for 2–6 weeks before chemoradiation therapy (CRT). Endpoints included apoptosis and proliferation rates, clinical response, and toxicity.Results:Versus placebo, lapatinib monotherapy did not significantly increase apoptosis detected by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labelling or caspase-3 assays. A statistically significant decrease in proliferation using Ki67 assay was observed (P=0.030). In a subset of 40 patients that received ⩾4 weeks of lapatinib or placebo, objective response rate (ORR) was 17% (n=4/24) vs 0% (n=0/16). In the lapatinib single-agent responders, all had EGFR overexpression, 50% had EGFR amplification, and 50% had HER2 expression by immunohistochemistry (including one patient with HER2 amplification). However, these patients showed variable modulation of apoptosis, proliferation, and phosphorylated EGFR on drug treatment. Following CRT, there was a statistically non-significant difference in ORR between lapatinib (70%) and placebo (53%). There was no clear correlation between changes in apoptosis or proliferation and response to chemoradiation. Mucosal inflammation, asthenia, odynophagia, and dysphagia were the most commonly reported adverse events with lapatinib.Conclusion:Short-term lapatinib monotherapy did not demonstrate apoptotic changes, but provided evidence of clinical activity in locally advanced SCCHN, and warrants further investigation in this disease.

Drug-induced liver chemistry abnormalities, primarily transaminase elevations, are commonly observed in pazopanib-treated patients. This meta-analysis characterises liver chemistry abnormalities associated with pazopanib. Data of pazopanib-treated patients from nine prospective trials were integrated (N=2080). Laboratory datasets were used to characterise the incidence, timing, recovery and patterns of liver events, and subsequent rechallenge with pazopanib. Severe cases of liver chemistry abnormalities were clinically reviewed. Multivariate analyses identified predisposing factors. Twenty percent of patients developed elevated alanine aminotransferase (ALT) >3×ULN. Incidence of peak ALT >3-5×ULN, >5-8×ULN, >8-20×ULN and >20×ULN was 8%, 5%, 5% and 1%, respectively. Median time to onset for all events was 42days; 91% of events were observed within 18weeks. Recovery rates based on peak ALT >3-5×ULN, >5-8×ULN, >8-20×ULN and >20×ULN were 91%, 90%, 90% and 64%, respectively. Median time from onset to recovery was 30days, but longer in patients without dose interruption. Based on clinical review, no deaths were associated with drug-induced liver injury. Overall, 38% of rechallenged patients had ALT elevation recurrence, with 9-day median time to recurrence. Multivariate analysis showed that older age was associated with development of ALT >8×ULN. There was no correlation between hypertension and transaminitis. Our data support the current guidelines on regular liver chemistry tests after initiation of pazopanib, especially during the first 9 or 10weeks, and also demonstrate the safety of rechallenge with pazopanib.

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BackgroundThere are variations in the proportions of head and neck cancers caused by the human papillomavirus (HPV) between countries and regions. It is unclear if these are true variations or due to different study designs and assays.MethodsWe tested formalin‐fixed paraffin‐embedded diagnostic biopsies for p16 immunohistochemistry and HPV‐DNA (by polymerase chain reaction [PCR] and in situ hybridization [ISH]) using validated protocols on samples from 801 patients with head and neck cancer recruited prospectively between 2006 and 2011 in 4 randomized controlled trials (RCTs).ResultsTwenty‐one percent of patients (170 of 801) showed both HPV‐DNA and p16‐positivity, detected almost exclusively in oropharyngeal cancer (55%; 15 of 302); and only 1% of the patients (5 of 499) with nonoropharyngeal cancer were HPV positive. HPV‐positive oropharyngeal cancer differed between Western and Eastern Europe (37%, 155 of 422 vs 6%, 8 of 144; p < .0001) and between Western Europe and Asia (37% vs 2%; 4 of 217; p < .0001). Other independent determinants of HPV positivity were tumor site and smoking.ConclusionThis is the first study to establish geographic variability as an independent risk factor in HPV‐positive oropharyngeal cancer prevalence, with higher prevalence in Western Europe. © 2016 The Authors Head & Neck Published by Wiley Periodicals, Inc. Head Neck 38: E1863–E1869, 2016

Businesses have an unrivalled ability to mobilize human, physical and financial capital, often manage large land holdings, and draw on resources and supply products that impact a wide array of ecosystems. Businesses therefore have the potential to make a substantial contribution to arresting declines in biodiversity and ecosystem services. To realize this potential, businesses require support from researchers in applied ecology to inform how they measure and manage their impacts on, and opportunities presented to them by, biodiversity and ecosystem services.We reviewed papers in leading applied ecology journals to assess the research contribution from existing collaborations involving businesses. We reviewed applications to, and grants funded by, the UK’s Natural Environment Research Council for evidence of public investment in such collaborations. To scope opportunities for expanding collaborations with businesses, we conducted workshops with three sectors (mining and quarrying, insurance and manufacturing) in which participants identified exemplar ecological research questions of interest to their sector.Ten to fifteen per cent of primary research papers in Journal of Applied Ecology and Ecological Applications evidenced business involvement, mostly focusing on traditional rural industries (farming, fisheries and forestry). The review of UK research council funding found that 35% of applications mentioned business engagement, while only 1% of awarded grants met stricter criteria of direct business involvement.Some questions identified in the workshops aim to reduce costs from businesses’ impacts on the environment and others to allow businesses to exploit new opportunities. Some questions are designed to inform long-term planning undertaken by businesses, but others would have more immediate commercial applications. Finally, some research questions are designed to streamline and make more effective those environmental policies that affect businesses.Business participants were forward-looking regarding ecological questions and research. For example, representatives from mining and quarrying companies emphasized the need to move beyond biodiversity to consider how ecosystems function, while those from the insurance sector stressed the importance of ecology researchers entering into new types of interdisciplinary collaboration.Synthesis and applications. Businesses from a variety of sectors demonstrated a clear interest in managing their impacts on, and exploiting opportunities created by, ecosystem services and biodiversity. To achieve this, businesses are asking diverse ecological research questions, but publications in leading applied ecology journals and research council funding reveal limited evidence of direct engagement with businesses. This represents a missed opportunity for ecological research findings to see more widespread application.