Clinical potential of oligonucleotide-based therapeutics in the respiratory system

The discovery of an ever-expanding plethora of coding and non-coding RNAs with nodal and causal roles in the regulation of lung physiology and disease is reinvigorating interest in the clinical utility of the oligonucleotide therapeutic class. This is strongly supported through recent advances in nucleic acids chemistry, synthetic oligonucleotide delivery and viral gene therapy that have succeeded in bringing to market at least three nucleic acid-based drugs. As a consequence, multiple new candidates such as RNA interference modulators, antisense, and splice switching compounds are now progressing through clinical evaluation. Here, manipulation of RNA for the treatment of lung disease is explored, with emphasis on robust pharmacological evidence aligned to the five pillars of drug development: exposure to the appropriate tissue, binding to the desired molecular target, evidence of the expected mode of action, activity in the relevant patient population and commercially viable value proposition.

Bevacizumab in NF2-related vestibular schwannomas: a nationally coordinated approach to delivery and prospective evaluation

Background: NF2 patients develop multiple nervous system tumors including bilateral vestibular schwannomas (VS). The tumors and their surgical treatment are associated with deafness, neurological disability, and mortality. Medical treatment with bevacizumab has been reported to reduce VS growth and to improve hearing. In addition to evaluating these effects, this study also aimed to determine other important consequences of treatment including patient-reported quality of life and the impact of treatment on surgical VS rates. Methods: Patients treated with bevacizumab underwent serial prospective MRI, audiology, clinical, CTCAE-4.0 adverse events, and NFTI-QOL quality-of-life assessments. Tumor volumetrics were classified according to the REiNs criteria and annual VS surgical rates reviewed. Results: Sixty-one patients (59% male), median age 25 years (range, 10–57), were reviewed. Median follow-up was 23 months (range, 3–53). Partial volumetric tumor response (all tumors) was seen in 39% and 51% had stabilization of previously growing tumors. Age and pretreatment growth rate were predictors of response. Hearing was maintained or improved in 86% of assessable patients. Mean NFTI-QOL scores improved from 12.0 to 10.7 (P < .05). Hypertension was observed in 30% and proteinuria in 16%. Twelve treatment breaks occurred due to adverse events. The rates of VS surgery decreased after the introduction of bevacizumab. Conclusion: Treatment with bevacizumab in this large, UK-wide cohort decreased VS growth rates and improved hearing and quality of life. The potential risk of surgical iatrogenic damage was also reduced due to an associated reduction in VS surgical rates. Ongoing follow-up of this cohort will determine the long-term benefits and risks of bevacizumab treatment.

Using a whole person approach to support people with cancer: a longitudinal, mixed methods service evaluation

Introduction: Improved models of care are needed to meet all the support needs of people with cancer, which encompass psychological, emotional, physical, spiritual, sexual, occupational, social and existential needs. The aim of this paper is to (1) evaluate short and long-term impacts of using a whole person approach to support people with cancer on the Living Well with the Impact of Cancer Course (LWC); (2) use these data to inform strategic decisions about future service provision at Penny Brohn UK. Methods: Longitudinal mixed-methods service evaluation (n=135). Data collected included health related quality of life (HRQoL) (FACIT-SpEx); Concerns (types and severity - MYCaW); lifestyle behaviour (bespoke questionnaire) and participants’ experiences over 12 months post course. Results: Statistically and clinically significant improvements from baseline - 12 months in severity of MYCaW Concerns (n=64; p<0.000) and mean total HRQoL (n=66; p<0.000). The majority of MYCaW concerns were ‘psychological and emotional’ and about participants’ wellbeing. Spiritual, emotional and functional wellbeing contributed most to HRQoL improvements at 12 months. Barriers to maintaining healthy lifestyle changes included lack of support from family and friends, time constraints, and returning to work. 3-6 months post-course was identified as the time when more support was most likely to be needed. Conclusions: Using a whole person approach for the LWC enabled the needs of participants to be met, and statistically and clinically significant improvements in HRQoL and MYCaW Concerns were reported. Qualitative data analysis explored how experiencing whole person support enabled participants to make and sustain healthy lifestyle changes associated with improved survivorship. Barriers experienced to making health behaviour change were also identified. These data then informed wider and more person-centred clinical provision to increase the maintenance of positive long-term behaviour changes. Comparison of whole person approaches to cancer treatment and support and standard care are now urgently needed.

Nutritional Evaluation and Optimisation in Neonates: a randomized, double-blind controlled trial of amino acid regimen and intravenous lipid composition in preterm parenteral nutrition

Background: Parenteral nutrition is central to the care of very immature infants. Current international recommendations favor higher amino acid intakes and fish oil–containing lipid emulsions. Objective: The aim of this trial was to compare 1) the effects of high [immediate recommended daily intake (Imm-RDI)] and low [incremental introduction of amino acids (Inc-AAs)] parenteral amino acid delivery within 24 h of birth on body composition and 2) the effect of a multicomponent lipid emulsion containing 30% soybean oil, 30% medium-chain triglycerides, 25% olive oil, and 15% fish oil (SMOF) with that of soybean oil (SO)-based lipid emulsion on intrahepatocellular lipid (IHCL) content. Design: We conducted a 2-by-2 factorial, double-blind, multicenter randomized controlled trial. Results: We randomly assigned 168 infants born at ,31 wk of gestation. We evaluated outcomes at term in 133 infants. There were no significant differences between Imm-RDI and Inc-AA groups for nonadipose mass [adjusted mean difference: 1.0 g (95% CI: 2108, 111 g; P = 0.98)] or between SMOF and SO groups for IHCL [adjusted mean SMOF:SO ratio: 1.1 (95% CI: 0.8, 1.6; P = 0.58]. SMOF does not affect IHCL content. There was a significant interaction (P = 0.05) between the 2 interventions for nonadipose mass. There were no significant interactions between group differences for either primary outcome measure after adjusting for additional confounders. Imm-RDI infants were more likely than Inc-AA infants to have blood urea nitrogen concentrations .7 mmol/L or .10 mmol/L, respectively (75% compared with 49%, P , 0.01; 49% compared with 18%, P , 0.01). Head circumference at term was smaller in the Imm-RDI group [mean difference: 20.8 cm (95% CI: 21.5, 20.1 cm; P = 0.02)]. There were no significant differences in any prespecified secondary outcomes, including adiposity, liver function tests, incidence of conjugated hyperbilirubinemia, weight, length, mortality, and brain volumes. Conclusion: Imm-RDI of parenteral amino acids does not benefit body composition or growth to term and may be harmful. This trial was registered at www.isrctn.com as ISRCTN29665319 and at eudract.ema.europa.eu as EudraCT 2009-016731-34.