Eating As Treatment (EAT): A Stepped-Wedge, Randomized Controlled Trial of a Health Behavior Change Intervention Provided by Dietitians to Improve Nutrition in Patients With Head and Neck Cancer Undergoing Radiation Therapy (TROG 12.03)

Purpose: Malnutrition in head and neck cancer (HNC) treatment is common and associated with poorer morbidity and mortality outcomes. This trial aimed to improve nutritional status during radiation therapy (RT) using a novel method of training dietitians to deliver psychological techniques to improve nutritional behaviors in patients with HNC. Methods and Materials: This trial used a stepped-wedge, randomized controlled design to assess the efficacy of the Eating As Treatment (EAT) program. Based on motivational interviewing and cognitive behavioral therapy, EAT was designed to be delivered by oncology dietitians and integrated into their clinical practice. During control steps, dietitians provided treatment as usual, before being trained in EAT and moving into the intervention phase. The training was principles based and sought to improve behavior-change skills rather than provide specific scripts. Patients recruited to the trial (151 controls, 156 intervention) were assessed at 4 time points (the first and the final weeks of RT, and 4 and 12 weeks afterward). The primary outcome was nutritional status at the end of RT as measured by the Patient-Generated Subjective Global Assessment. Results: Patients who received the EAT intervention had significantly better scores on the primary outcome of nutritional status at the critical end-of-treatment time point (β = −1.53 [−2.93 to −.13], P =.03). Intervention patients were also significantly more likely than control patients to be assessed as well-nourished at each time point, lose a smaller percentage of weight, have fewer treatment interruptions, present lower depression scores, and report a higher quality of life. Although results were not statistically significant, patients who received the intervention had fewer and shorter unplanned hospital admissions. Conclusions: This trial is the first of its kind to demonstrate the effectiveness of a psychological intervention to improve nutrition in patients with HNC who are receiving RT. The intervention provides a means to ameliorate malnutrition and the important related outcomes and consequently should be incorporated into standard care for patients receiving RT for HNC

“Quitlink”—A Randomized Controlled Trial of Peer Worker Facilitated Quitline Support for Smokers Receiving Mental Health Services: Study Protocol

Introduction: Although smokers with severe mental illnesses (SSMI) make quit attempts at comparable levels to other smokers, fewer are successful in achieving smoking cessation. Specialized smoking cessation treatments targeting their needs can be effective but have not been widely disseminated. Telephone delivered interventions, including by quitlines, show promise. However, few SSMI contact quitlines and few are referred to them by health professionals. Mental health peer workers can potentially play an important role in supporting smoking cessation. This study will apply a pragmatic model using peer workers to engage SSMI with a customized quitline service, forming the “Quitlink” intervention.Methods: A multi-center prospective, cluster-randomized, open, blinded endpoint (PROBE) trial. Over 3 years, 382 smokers will be recruited from mental health services in Victoria, Australia. Following completion of baseline assessment, a brief intervention will be delivered by a peer worker. Participants will then be randomly allocated either to no further intervention, or to be referred and contacted by the Victorian Quitline and offered a targeted 8-week cognitive behavioral intervention along with nicotine replacement therapy (NRT). Follow-up measures will be administered at 2-, 5-, and 8-months post-baseline. The primary outcome is 6 months continuous abstinence from end of treatment with biochemical verification. Secondary outcomes include 7-day point prevalence abstinence from smoking, increased quit attempts, and reductions in cigarettes per day, cravings and withdrawal, mental health symptoms, and other substance use, and improvements in quality of life. We will use a generalized linear mixed model (linear regression for continuous outcomes and logistic regression for dichotomous outcomes) to handle clustering and the repeated measures at baseline, 2-, 5-, and 8-months; individuals will be modeled as random effects, cluster as a random effect, and group assignment as a fixed effect.Discussion: This is the first rigorously designed RCT to evaluate a specialized quitline intervention accompanied by NRT among SSMI. The study will apply a pragmatic model to link SSMI to the Quitline, using peer workers, with the potential for wide dissemination.Clinical Trial Registration:Trial Registry: The trial is registered with ANZCTR (www.anzctr.org.au): ACTRN12619000244101 prior to the accrual of the first participant and updated regularly as per registry guidelines.Trial Sponsor: University of Newcastle, NSW, Australia

Spermatogenesis-Specific Features of the Meiotic Program in Caenorhabditis elegans

In most sexually reproducing organisms, the fundamental process of meiosis is implemented concurrently with two differentiation programs that occur at different rates and generate distinct cell types, sperm and oocytes. However, little is known about how the meiotic program is influenced by such contrasting developmental programs. Here we present a detailed timeline of late meiotic prophase during spermatogenesis in Caenorhabditis elegans using cytological and molecular landmarks to interrelate changes in chromosome dynamics with germ cell cellularization, spindle formation, and cell cycle transitions. This analysis expands our understanding C. elegans spermatogenesis, as it identifies multiple spermatogenesis-specific features of the meiotic program and provides a framework for comparative studies. Post-pachytene chromatin of spermatocytes is distinct from that of oocytes in both composition and morphology. Strikingly, C. elegans spermatogenesis includes a previously undescribed karyosome stage, a common but poorly understood feature of meiosis in many organisms. We find that karyosome formation, in which chromosomes form a constricted mass within an intact nuclear envelope, follows desynapsis, involves a global down-regulation of transcription, and may support the sequential activation of multiple kinases that prepare spermatocytes for meiotic divisions. In spermatocytes, the presence of centrioles alters both the relative timing of meiotic spindle assembly and its ultimate structure. These microtubule differences are accompanied by differences in kinetochores, which connect microtubules to chromosomes. The sperm-specific features of meiosis revealed here illuminate how the underlying molecular machinery required for meiosis is differentially regulated in each sex

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Smoking cessation interventions for people living in rural and remote areas: a systematic review protocol

Introduction Smoking rates among people living in rural and remote areas are higher and quit rates are lower over the past 10 years compared with people living in suburban and urban areas. Higher smoking rates contribute to greater tobacco-related disease and morbidity in rural and remote areas. Physical and social isolation, greater exposure to pro-tobacco marketing, pro-tobacco social norms, and lower socioeconomic and educational levels are contributing to these higher smoking rates and lower quit rates. Smoking cessation interventions for people in rural and remote areas have been conducted, however little is known about their effectiveness or their mechanisms of action as well as the quality of such research. Behaviour change techniques (BCTs) are mechanisms of action derived from behaviour change theory, such as goal setting and reward. Improved understanding of the contribution of BCTs for smoking cessation in the rural and remote population will support future intervention development. We aim to review the literature on smoking cessation interventions for people living in rural and remote areas to inform evidence about intervention effectiveness and mechanisms of action.Methods and analysis We will conduct a systematic review using seven scientific databases (EMBASE, MedLine, PsycINFO, CINAHL, Cochrane, Informit Health and Scopus). We will include peer-reviewed journal articles published in English that examine a smoking cessation intervention delivered to people living in rural and remote areas in the USA, Canada and Australia. We will examine outcome data relating to intervention effectiveness (eg, point prevalence abstinence or continuous abstinence), as well as the BCTs used in included interventions and their relationship with intervention outcomes. We will also assess the feasibility, acceptability and quality of research interventions of included articles, and provide graded recommendations based on the review outcomes. Data will be synthesised using narrative approaches and interpreted using content analysis.Ethics and dissemination Ethics was not required for this systematic review. The results will be disseminated through peer-reviewed publication and at conferences by presentations.PROSPERO registration number 177398

‘Having the mask on didn't worry me until … they clamped my head down so I wouldn't move’: A qualitative study exploring anxiety in patients with head and neck cancer during radiation therapy

ABSTRACT Introduction More than 20% of patients undergoing radiation therapy for head and neck cancer report anxiety specifically related to the immobilisation mask, a tight‐fighting mask patients are required to wear for the duration of each treatment session. However, limited research has investigated this from the patient perspective. The aim of this study was to better understand patient experiences of mask anxiety during head and neck cancer radiation therapy and to explore patient attitudes toward potential strategies that may reduce mask anxiety during this treatment. Methods Five patients with head and neck cancer, who had self‐reported mask anxiety during radiation therapy, participated in semi‐structured, qualitative interviews exploring their experiences of anxiety and suggestions for reducing anxiety. A codebook thematic analysis was conducted. Results Six main themes were identified: (1) triggers of anxiety; (2) adjusting to radiation therapy; (3) education about the mask; (4) coping; (5) motivation and (6) improving the patient experience. Conclusion Findings from these interviews provide valuable insight into how and when healthcare providers may be able to assist patients to manage mask anxiety. Recommendations include increased communication from health care providers; delivery of visual information to improve patient preparedness; exposure/opportunities to interact with the masks prior to treatment commencing and increased control of music/soundtrack selection. However, a limitation of this study is the small sample size and further research is warranted

Assessing adherence, competence and differentiation in a stepped-wedge randomised clinical trial of a complex behaviour change intervention

A key challenge in behavioural medicine is developing interventions that can be delivered adequately (i.e., with fidelity) within real-world consultations. Accordingly, clinical trials should (but tend not to) report what is actually delivered (adherence), how well (competence) and the distinction between intervention and comparator conditions (differentiation).To address this important clinical and research priority, we apply best practice guidelines to evaluate fidelity within a real-world, stepped-wedge evaluation of "EAT: Eating As Treatment", a new dietitian delivered health behaviour change intervention designed to reduce malnutrition in head and neck cancer (HNC) patients undergoing radiotherapy.Dietitians ( = 18) from five Australian hospitals delivered a period of routine care and following a randomly determined order each site received training and began delivering the EAT Intervention. A 20% random stratified sample of audio-recorded consultations (control = 196; intervention = 194) was coded by trained, independent, raters using a study specific checklist and the Behaviour Change Counselling Inventory. Intervention adherence and competence were examined relative to apriori benchmarks. Differentiation was examined by comparing control and intervention sessions (adherence, competence, non-specific factors, and dose), via multiple linear regression, logistic regression, or mixed-models.Achievement of adherence benchmarks varied. The majority of sessions attained competence. Post-training consultations were clearly distinct from routine care regarding motivational and behavioural, but not generic, skills.Although what level of fidelity is "good enough" remains an important research question, findings support the real-world feasibility of integrating EAT into dietetic consultations with HNC patients and provide a foundation for interpreting treatment effects