Adherence to prescribing restrictions for HER2-positive metastatic breast cancer in Australia: A national population-based observational study (2001-2016)

Background: Targeted cancer therapy is often complex, involving multiple agents and chemotherapeutic partners. In Australia, prescribing restrictions are put in place to reflect existing evidence of cost-effectiveness of these medicines. As therapeutic options continue to expand, these restrictions may not be perceived to align with best practice and it is not known if their use in the real-world clinic adheres to these restrictions. We examined the treatment of women receiving trastuzumab for HER2-positive metastatic breast cancer (HER2+MBC) to determine the extent to which treatment adhered to national prescribing restrictions. Patients and methods: Our population-based, retrospective cohort study used dispensing records for every Australian woman initiating publicly-subsidised trastuzumab for HER2+MBC between 2001±2013, followed through 2016. We used group-based trajectory models (GBTMs) to cluster patients, first on their patterns of trastuzumab exposure, and then on their patterns of lapatinib and chemotherapy exposure. We described the characteristics of patients within each cluster, and examined their treatments and combinations of treatments to determine restriction adherence. Results: Of 5,052 patients initiating trastuzumab, 1,795 (36%) received at least one non-adherent HER2-targeted treatment. The most common non-adherent treatments were trastuzumab combinations involving vinorelbine (24% of non-adherent treatments); capecitabine (24%); and anthracyclines (10%). Non-adherent lapatinib use was observed in 4% of patients. GBTM identified three trastuzumab exposure clusters, each containing three further subclusters. The largest proportions of non-adherent treatments were in sub-clusters with longer trastuzumab exposure and more non-taxane chemotherapy. Patients in these sub-clusters were younger than those in sub-clusters with less non-adherent treatment. Conclusions: Our study highlights that, even during the relatively simpler treatment era of our study period, a substantial amount of treatment did not adhere to prescribing restrictions. As more trials are conducted exploring pertuzumab and T-DM1 in combination with different chemotherapies and other HER2-targeted therapies, the regulation and funding of HER2-targeted treatment will become more challenging

Fish and Wildlife Benefits of the Wildlife Habitat Incentives Program

Th e Wildlife Habitat Incentives Program (WHIP) is a voluntary program that encourages the establishment and enhancement of a wide variety of fish and wildlife habitats of national, state, tribal, or local significance. Through voluntary agreements, the Natural Resources Conservation Service (NRCS) provides financial and technical assistance to participants who installed habitat restoration and management practices. Since 1998, nearly $150 million has been dedicated to the program and over 2.8 million acres involving over 18,000 contracts have been enrolled. A wide range of habitat-enhancement actions are cost-shared through the program, affecting hundreds of target and non-target species. While few quantitative data exist describing how fish and wildlife have responded to terrestrial and aquatic habitats enrolled in the program, the popularity of WHIP among participants and funding partners and anecdotal evidence imply that tangible benefits to target species are being realized. Additional studies are needed to better understand how WHIP projects affect local habitat use by and population response of target and non-target species

Use and outcomes of targeted therapies in early and metastatic HER2-positive breast cancer in Australia: Protocol detailing observations in a whole of population cohort

Background: The management of human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) has changed dramatically with the introduction and widespread use of HER2-targeted therapies. However, there is relatively limited real-world information on patterns of use, effectiveness and safety in whole of population cohorts. The research programme detailed in this protocol will generate evidence on the prescribing patterns, safety monitoring and outcomes of patients with BC treated with HER2- targeted therapies in Australia. Methods/design: Our ongoing research programme will involve a series of retrospective cohort studies that include every patient accessing Commonwealth-funded HER2-targeted therapies for the treatment of early BC and advanced BC in Australia. At the time of writing, our cohorts consist of 11 406 patients with early BC and 5631 with advanced BC who accessed trastuzumab and lapatinib between 2001 and 2014. Pertuzumab and trastuzumab emtansine were publicly funded for metastatic BC in 2015, and future data updates will include patients accessing these medicines. We will use dispensing claims for cancer and other medicines, medical service claims and demographics data for each patient accessing HER2- targeted therapies to undertake this research. Ethics and dissemination: Ethics approval has been granted by the Population Health Service Research Ethics Committee and data access approval has been granted by the Australian Department of Human Services (DHS) External Review Evaluation Committee. Our findings will be reported in peer-reviewed publications, conference presentations and policy forums. By providing detailed information on the use and outcomes associated with HER2-targeted therapies in a national cohort treated in routine clinical care, our research programme will better inform clinicians and patients about the real-world use of these treatments and will assist third-party payers to better understand the use and economic costs of these treatments

Pediatric Sacral Nerve Stimulator Explanation due to Complications or Cure: A Survival Analysis

Introduction Historically, there have been few treatment options for children with severe, refractory bladder and bowel dysfunction (BBD). Sacral neuromodulation (SNM) continues to show promising results in this challenging pediatric population with recalcitrant lower urinary tract symptoms. At our institution, we have begun offering explantation to those with persistent improvement after >6 months of having device turned off. We hypothesized that 1.) SNM explantation for cure increases with extended follow-up, and 2.) those explanted for cure would have improved symptoms and quality of life when compared to those explanted for complication. Materials & Methods We retrospectively reviewed all consecutive patients <18 years old who underwent SNM placements at our institution (2012-2017). We excluded those without the second stage procedure. Reasons for device explantation were categorized as: cure (resolution of symptoms with the device turned off for at least 6 months), or a complication (e.g. infection, need for MRI, or pain). Non-parametric tests and survival analysis were used for analysis to account for differential follow-up time. Of those explanted, surveys were electronically sent to assess BBD severity, and overall quality of life. Results Of 67 children who underwent a first stage procedure, 62 (92.5%) underwent a second stage procedure. 61 met inclusion criteria (68.9% female, 29.5 % with previous filum section, median age at implantation 10.3 years old). During follow-up (median 2.3 years), 12 patients (19.7 %) had the SNM exchanged/revised due to lead fracture/breakage and return of urinary symptoms. To date, 50 patients remain with their SNM implanted, and 11 have been explanted. Adjusting for follow-up time, the risk of explantation was 6.5% at 2 years (2.2% for cure, 4.3% for complications) (Figure 1). Explantation increased to 24.5% at 3 years (16.5% for cure, 8.0% for complications) and 40.4% at 4 years (32.4% for cure, 8.0% for complications). Questionnaires were collected on patients post explant (median 2.2 years), with improvement in those explanted for cure compared to complication (Figure 2). Discussion SNM explantation for cure is a novel concept previously not described in the literature. Limitations of this study include the relatively small numbers, and lack of objective data in the cohort that remains with SNM device implanted. Conclusion SNM is a safe, viable option for the pediatric patient with refractory bladder dysfunction. Furthermore, SNM explantation for cure is an option with increasing likelihood after two years

Managing idiopathic intracranial hypertension in pregnancy: practical advice

Idiopathic intracranial hypertension (IIH) is more common in women of reproductive age who have obesity, yet there is little information on its management specifically in pregnancy. Women with IIH should plan their pregnancy including discussing contraception before pregnancy, recognising that hormonal contraceptives are not contraindicated. Potentially teratogenic medications including acetazolamide and topiramate are not recommended during pregnancy or in those with immediate plans to conceive; prescribing acetazolamide in pregnancy must only follow discussion with the patient and their obstetrician. Ideally, patients should aim to achieve disease remission or control before pregnancy, through optimising their weight. Although weight gain is expected in pregnancy, excessive weight gain may exacerbate IIH and increase maternal and fetal complications; evidence-based recommendations for non-IIH pregnancies may help in guiding optimal gestational weight gain. The vast majority of women with IIH can have a normal vaginal delivery, with spinal or epidural anaesthesia if needed, provided the papilloedema is stable or the IIH is in remission

Interleukin 15 Primes Natural Killer Cells to Kill via NKG2D and cPLA2 and This Pathway Is Active in Psoriatic Arthritis

NK cells are large granular lymphocytes that form a critical component of the innate immune system, whose functions include the killing of cells expressing stress-induced molecules. It is increasingly accepted that despite being considered prototypical effector cells, NK cells require signals to reach their full cytotoxic potential. We previously showed that IL-15 is capable of arming CD8 effector T cells to kill independently of their TCR via NKG2D in a cPLA2-dependent process. As NK cells also express NKG2D, we wanted to investigate whether this pathway functioned in an analogous manner and if resting NK cells could be primed to the effector phase by IL-15. Furthermore, to establish relevance to human disease we studied a possible role for this pathway in the pathogenesis of psoriatic arthritis, since there are aspects of this disease that suggest a potential effector role for the innate immune system. We found that PsA patients had upregulated IL-15 and MIC in their affected synovial tissues, and that this unique inflammatory environment enabled NK cell activation and killing via NKG2D and cPLA2. Moreover, we were able to reproduce the phenotype of joint NK cells from blood NK cells by incubating them with IL-15. Altogether, these findings suggest a destructive role for NK cells when activated by environmental stress signals during the pathogenesis of PsA and demonstrate that IL-15 is capable of priming resting NK cells in tissues to the effector phase.</p

Interleukin 15 Primes Natural Killer Cells to Kill via NKG2D and cPLA2 and This Pathway Is Active in Psoriatic Arthritis

NK cells are large granular lymphocytes that form a critical component of the innate immune system, whose functions include the killing of cells expressing stress-induced molecules. It is increasingly accepted that despite being considered prototypical effector cells, NK cells require signals to reach their full cytotoxic potential. We previously showed that IL-15 is capable of arming CD8 effector T cells to kill independently of their TCR via NKG2D in a cPLA2-dependent process. As NK cells also express NKG2D, we wanted to investigate whether this pathway functioned in an analogous manner and if resting NK cells could be primed to the effector phase by IL-15. Furthermore, to establish relevance to human disease we studied a possible role for this pathway in the pathogenesis of psoriatic arthritis, since there are aspects of this disease that suggest a potential effector role for the innate immune system. We found that PsA patients had upregulated IL-15 and MIC in their affected synovial tissues, and that this unique inflammatory environment enabled NK cell activation and killing via NKG2D and cPLA2. Moreover, we were able to reproduce the phenotype of joint NK cells from blood NK cells by incubating them with IL-15. Altogether, these findings suggest a destructive role for NK cells when activated by environmental stress signals during the pathogenesis of PsA and demonstrate that IL-15 is capable of priming resting NK cells in tissues to the effector phase

Metastatic breast cancer incidence, site and survival in Australia, 2001-2016: A population-based health record linkage study protocol

Introduction: Advances in systemic therapy for early and metastatic breast cancer (BC) over the last two decades have improved patients’ survival, but their impact on metastatic disease outcomes at a population level is not well described. The aim of this study is to investigate changes in the incidence, site and survival of metastatic disease for women with a first diagnosis of BC in 2001– 2002 vs 2006–2007. Methods and analysis: Population-based retrospective cohort study of women with first primary invasive BC registered in the New South Wales (NSW) Cancer Registry in 2001–2002 and 2006–2007. We will use linked records from NSW hospitals, dispensed medicines, outpatient services and death registrations to determine: women’s demographic and tumour characteristics; treatments received; time to first distant metastasis; site of first metastasis and survival. We will use the Kaplan-Meier method to estimate cumulative incidence of distant metastasis, distant recurrence-free interval and postmetastasis survival by extent of disease at initial diagnosis, site of metastasis and treatment-defined tumour receptor type (hormone receptor-positive, human epidermal growth factor receptor-2-positive, triple negative). We will use Cox proportional hazards regression to estimate the relative effects of prognostic factors, and we will compare systemic therapy patterns by area-of- residence and area-level socioeconomic status to examine equity of access to healthcare. Ethics and dissemination: Research ethics committee approval was granted by the Australian Institute of Health and Welfare (#EO2017/2/255), NSW Population and Health Services (#HREC/17/CIPHS/19) and University of Notre Dame Australia (#0 17 144S). We will disseminate research findings to oncology, BC consumer and epidemiology audiences through national and international conference presentations, lay summaries to BC consumer groups and publications in international peer-reviewed oncology and cancer epidemiology journals