Paediatric strategy forum for medicinal product development of PI3-K, mTOR, AKT and GSK3ß inhibitors in children and adolescents with cancer.

Phosphatidylinositol 3-kinase (PI3-K) signalling pathway is a crucial path in cancer for cell survival and thus represents an intriguing target for new paediatric anti-cancer drugs. However, the unique clinical toxicities of targeting this pathway (resulting in hyperglycaemia) difficulties combining with chemotherapy, rarity of mutations in childhood tumours and concomitant mutations have resulted in major barriers to clinical translation of these inhibitors in treating both adults and children. Mutations in PIK3CA predict response to PI3-K inhibitors in adult cancers. The same mutations occur in children as in adults, but they are significantly less frequent in paediatrics. In children, high-grade gliomas, especially diffuse midline gliomas (DMG), have the highest incidence of PIK3CA mutations. New mutation-specific PI3-K inhibitors reduce toxicity from on-target PI3-Kα wild-type activity. The mTOR inhibitor everolimus is approved for subependymal giant cell astrocytomas. In paediatric cancers, mTOR inhibitors have been predominantly evaluated by academia, without an overall strategy, in empiric, mutation-agnostic clinical trials with very low response rates to monotherapy. Therefore, future trials of single agent or combination strategies of mTOR inhibitors in childhood cancer should be supported by very strong biological rationale and preclinical data. Further preclinical evaluation of glycogen synthase kinase-3 beta inhibitors is required. Similarly, even where there is an AKT mutation (∼0.1 %), the role of AKT inhibitors in paediatric cancers remains unclear. Patient advocates strongly urged analysing and conserving data from every child participating in a clinical trial. A priority is to evaluate mutation-specific, central nervous system-penetrant PI3-K inhibitors in children with DMG in a rational biological combination. The choice of combination, should be based on the genomic landscape e.g. PTEN loss and resistance mechanisms supported by preclinical data. However, in view of the very rare populations involved, innovative regulatory approaches are needed to generate data for an indication.

Genetic Silencing of AKT Induces Melanoma Cell Death via mTOR Suppression.

Aberrant activation of the PI3K-AKT pathway is common in many cancers, including melanoma, and AKT1, 2 and 3 (AKT1-3) are bona fide oncoprotein kinases with well-validated downstream effectors. However, efforts to pharmacologically inhibit AKT have proven to be largely ineffective. In this study, we observed paradoxical effects following either pharmacologic or genetic inhibition of AKT1-3 in melanoma cells. Although pharmacological inhibition was without effect, genetic silencing of all three AKT paralogs significantly induced melanoma cell death through effects on mTOR. This phenotype was rescued by exogenous AKT1 expression in a kinase-dependent manner. Pharmacological inhibition of PI3K and mTOR with a novel dual inhibitor effectively suppressed melanoma cell proliferation in vitro and inhibited tumor growth in vivo. Furthermore, this single-agent-targeted therapy was well-tolerated in vivo and was effective against MAPK inhibitor-resistant patient-derived melanoma xenografts. These results suggest that inhibition of PI3K and mTOR with this novel dual inhibitor may represent a promising therapeutic strategy in this disease in both the first-line and MAPK inhibitor-resistant setting.

HIV Treatment Outcomes in POP-UP: Drop-in HIV Primary Care Model for People Experiencing Homelessness.

BACKGROUND: People with HIV experiencing homelessness have low rates of viral suppression, driven by sociostructural barriers and traditional care system limitations. Informed by the capability-opportunity-motivation-behavior (COM-B) model and patient preference research, we developed POP-UP, an integrated drop-in (nonappointment-based) HIV clinic with wrap-around services for persons with housing instability and viral nonsuppression in San Francisco. METHODS: We report HIV viral suppression (VS; <200 copies/mL), care engagement, and mortality at 12 months postenrollment. We used logistic regression to determine participant characteristics associated with VS. RESULTS: We enrolled 112 patients with viral nonsuppression and housing instability: 52% experiencing street-homelessness, 100% with a substance use disorder, and 70% with mental health diagnoses. At 12 months postenrollment, 70% had ≥1 visit each 4-month period, although 59% had a 90-day care gap; 44% had VS, 24% had viral nonsuppression, 23% missing, and 9% died (6 overdose, 2 AIDS-associated, 2 other). No baseline characteristics were associated with VS. CONCLUSIONS: The POP-UP low-barrier HIV care model successfully reached and retained some of our clinic's highest-risk patients. It was associated with VS improvement from 0% at baseline to 44% at 12 months among people with housing instability. Care gaps and high mortality from overdose remain major challenges to achieving optimal HIV treatment outcomes in this population.

Evaluation of the POP-UP programme: a multicomponent model of care for people living with HIV with homelessness or unstable housing.

OBJECTIVE: Homelessness is the greatest risk factor for HIV viremia in San Francisco. Innovative care models for people with HIV (PWH) with homelessness or unstable housing (HUH) are needed to address this inequity. We developed a novel low-barrier clinic-based program for PWH-HUH in an urban safety-net clinic ('POP-UP') and report outcomes on care engagement and viral suppression. DESIGN: A prospective cohort study. SETTING: San Francisco General Hospital HIV Clinic (Ward 86). PARTICIPANTS: We enrolled PWH who are HUH, viraemic and for whom usual care is not working (at least one missed primary care appointment and at least two drop-in visits at Ward 86 in the last year). INTERVENTION: POP-UP provides drop-in comprehensive primary care, housing assistance and case management, financial incentives and patient navigation with frequent contact. MAIN OUTCOME MEASURES: We describe uptake of eligible patients into POP-UP, and cumulative incidence of antiretroviral therapy (ART) initiation, return to care and virologic suppression 6 months post-enrolment, estimated via Kaplan--Meier. RESULTS: Out of 192 referred patients, 152 were eligible, and 75 enrolled. All 75 were off ART and viraemic; 100% had a substance use disorder; and 77% had a mental health diagnosis. Over three-quarters restarted ART within 7 days of enrolment, and 91% returned for follow-up within 90 days. The cumulative incidence of viral suppression at 6 months was 55% (95% confidence interval 43-68). CONCLUSION: A novel care model for PWH-HUH demonstrates early success in engaging viraemic patients in care and improving viral suppression. Low-barrier, high-contact primary care programmes offering comprehensive services and incentives may improve outcomes for this vulnerable population.

Improving Patient Preparedness and Confidence in Discussing Advance Directives for End-of-Life Care with Health Care Providers in the United States and Japan.

BACKGROUND: The low completion rate of advance directives (ADs) has received attention in Japan and the United States, as policy makers and health care professionals face aging populations with multiple comorbidities. Among the barriers to AD planning, cultural values and attitudes appear to be particularly influential. A comparison of culturally distinct societies provides a deeper understanding of these barriers. Through such an approach, this study identifies strategies for increasing AD planning among late-middle-age Japanese and US individuals. METHODS: After giving informed consent for the Institutional Review Board-approved study, Japanese and US respondents (45-65 y; 50% female) without ADs completed a language-appropriate online survey. Participants were asked to review a decision aid as part of a scenario-based physician consultation regarding artificial nutrition and hydration (ANH). Hypotheses were analyzed using multigroup structural equation modeling. RESULTS: Important similarities were identified across the 2 groups. After reviewing the decision aid, both samples strongly preferred "no ANH." Respondents who strongly valued either self-reliance or interpersonal relationships experienced greater preparedness for AD planning. In both countries, greater decision preparedness and positive death attitude predicted greater confidence to discuss care options with a provider. Finally, cultural values predicted preference for family participation: respondents with a strong interdependent self-concept desired more family involvement, whereas high independents preferred less. CONCLUSIONS: Findings indicate the importance of documenting care preferences and accounting for individual differences. To increase AD adoption, providers should identify patient segments likely to benefit most from the interventions. Targeting individuals in both countries who value self-reliance and interpersonal relationships appears to be a good place to begin. Such individuals can be identified clinically through administration of validated measures used in this study.

Culture, Self, and Medical Decision Making in Australia and China: A Structural Model Analysis.

Objective. To explore and compare the influences of individual-level cultural values and personal attitudinal values on the desire for medical information and self-involvement in decision making in Australia and China. Methods. A total of 288 and 291 middle-aged adults from Australia and China, respectively, completed an online survey examining cultural and personal values, and their desired level of self-influence on medical decision making. Structural equation modeling was used to test 15 hypotheses relating to the effects of cultural and personal antecedents on the individual desire for influence over medical decision making. Results. Similar factors in both Australia and China (total variance explained: Australia 29%; China 35%) predicted desire for medical information, with interdependence (unstandardized path coefficient ßAustralia = 0.102, P = 0.014; ßChina = 0.215, P = 0.001), independence (ßAustralia = 0.244, P < 0.001; ßChina = 0.123, P = 0.037), and health locus of control (ßAustralia = -0.140, P = 0.018; ßChina = -0.138, P = 0.007) being significant and positive predictors. A desire for involvement in decisions was only predicted by power distance, which had an opposite effect of being negative for Australia and positive for China (total variance explained: Australia 11%; China 5%; ßAustralia = 0.294, P < 0.001; China: ßChina = -0.190, P = 0.043). National culture moderated the effect of independence on desire for medical information, which was stronger in Australia than China (Z score = 1.687, P < 0.05). Conclusions. Study results demonstrate that in both countries, desire for medical information can be influenced by individual-level cultural and personal values, suggesting potential benefits of tailoring health communication to personal mindsets to foster informed decision making. The desired level of self-involvement in decision making was relatively independent of other cultural and personal values in both countries, suggesting caution against cultural stereotypes. Study findings also suggest that involvement preferences in decision making should be considered separately from information needs at the clinical encounter.

The effects of culturally targeted patient decision aids on medical consultation preparation for Hispanic women in the U.S.: Results from four randomized experiments.

RATIONALE: Do culturally targeted patient decision aids (DAs) better prepare lower-middle and middle-class Hispanic American women for medical decision making compared to DAs designed for the general population? Health promotion evidence indicates that inclusion of cultural values, imagery, linguistics, and health data in a DA will improve ethnic patients' preparation relative to a generic DA; yet, this hypothesis remains untested. METHOD: Four experiments examined consultation preparation effects of culturally targeted versus generic DAs for Hispanic women living in the United States. Drawing on highly rated online DAs, an experienced Hispanic content developer and Hispanic focus groups worked with researchers to develop culturally targeted digital DAs. Online panels of self-identified Hispanic women in the U.S. were randomly assigned to a targeted or generic DA as part of a scenario-based physician consultation for advanced diabetes (Study 1) or early stage breast cancer (Studies 2-4). RESULTS: Manipulation checks showed high awareness of cultural information in the targeted DA group. Despite efforts to rule out confounds that could account for null effects, DA cultural targeting did not increase knowledge, decision preparedness, or empowerment or reduce decision conflict in the four randomized experiments. Only individual difference variables (e.g., group interdependence) consistently predicted enhanced DA consultation preparation effects. Related research indicates that culture at the group level may exert less influence when individuals think deliberatively, feel less constrained by limited resources such as time, understand processing objectives, and/or are primed with task-specific schema/norms. CONCLUSION: Given deeper deliberation and clearly primed processing objectives, personal experiences and task-related schema/norms may have significantly reduced the effects of cultural targeting. Consistent findings from four studies suggest that culturally targeted DAs may not better prepare Hispanic women in the U.S. for medical decision making than generic versions designed for the broader population.

Who Decides: Me or We? Family Involvement in Medical Decision Making in Eastern and Western Countries.

BACKGROUND: Research suggests that desired family involvement (FI) in medical decision making may depend on cultural values. Unfortunately, the field lacks cross-cultural studies that test this assumption. As a result, providers may be guided by incomplete information or cultural biases rather than patient preferences. METHODS: Researchers developed 6 culturally relevant disease scenarios varying from low to high medical seriousness. Quota samples of approximately 290 middle-aged urban residents in Australia, China, Malaysia, India, South Korea, Thailand, and the USA completed an online survey that examined desired levels of FI and identified individual difference predictors in each country. All reliability coefficients were acceptable. Regression models met standard assumptions. RESULTS: The strongest finding across all 7 countries was that those who desired higher self-involvement (SI) in medical decision making also wanted lower FI. On the other hand, respondents who valued relational-interdependence tended to want their families involved - a key finding in 5 of 7 countries. In addition, in 4 of 7 countries, respondents who valued social hierarchy desired higher FI. Other antecedents were less consistent. CONCLUSION: These results suggest that it is important for health providers to avoid East-West cultural stereotypes. There are meaningful numbers of patients in all 7 countries who want to be individually involved and those individuals tend to prefer lower FI. On the other hand, more interdependent patients are likely to want families involved in many of the countries studied. Thus, individual differences within culture appear to be important in predicting whether a patient desires FI. For this reason, avoiding culture-based assumptions about desired FI during medical decision making is central to providing more effective patient centered care.

A cultural neuroscience perspective on North Korean strategic culture: Implications for tailored deterrence.

Given the complexity of the current nuclear age and the absence of work on deterrence under true multipolarity, interdisciplinary models can provide new perspectives on tailored deterrence. Drawing from recent findings in the life sciences, this article offers a cultural neuroscience approach to deterrence decision-making, with special attention given to the ways in which culture interacts with cognition and the security environment to shape behavioral outcomes during conflict. Since North Korea remains largely a "black box" in international relations, a cultural neuroscience perspective can provide valuable insight into the effects of cultural conditioning on perception and cognition within the context of nuclear deterrence on the Korean Peninsula. Through an analysis of the bureaucratic and military structures, leadership characteristics, and institutional landscapes shaping North Korean strategic culture, this article examines the influences of historical memory and cultural values, such as collectivism, honor, and face-saving, on political decision-making in Pyongyang.

Anamorelin in patients with non-small-cell lung cancer and cachexia (ROMANA 1 and ROMANA 2): results from two randomised, double-blind, phase 3 trials.

BACKGROUND: Patients with advanced cancer frequently experience anorexia and cachexia, which are associated with reduced food intake, altered body composition, and decreased functionality. We assessed anamorelin, a novel ghrelin-receptor agonist, on cachexia in patients with advanced non-small-cell lung cancer and cachexia. METHODS: ROMANA 1 and ROMANA 2 were randomised, double-blind, placebo-controlled phase 3 trials done at 93 sites in 19 countries. Patients with inoperable stage III or IV non-small-cell lung cancer and cachexia (defined as ≥5% weight loss within 6 months or body-mass index <20 kg/m(2)) were randomly assigned 2:1 to anamorelin 100 mg orally once daily or placebo, with a computer-generated randomisation algorithm stratified by geographical region, cancer treatment status, and weight loss over the previous 6 months. Co-primary efficacy endpoints were the median change in lean body mass and handgrip strength over 12 weeks and were measured in all study participants (intention-to-treat population). Both trials are now completed and are registered with ClinicalTrials.gov, numbers NCT01387269 and NCT01387282. FINDINGS: From July 8, 2011, to Jan 28, 2014, 484 patients were enrolled in ROMANA 1 (323 to anamorelin, 161 to placebo), and from July 14, 2011, to Oct 31, 2013, 495 patients were enrolled in ROMANA 2 (330 to anamorelin, 165 to placebo). Over 12 weeks, lean body mass increased in patients assigned to anamorelin compared with those assigned to placebo in ROMANA 1 (median increase 0·99 kg [95% CI 0·61 to 1·36] vs -0·47 kg [-1·00 to 0·21], p<0·0001) and ROMANA 2 (0·65 kg [0·38 to 0·91] vs -0·98 kg [-1·49 to -0·41], p<0·0001). We noted no difference in handgrip strength in ROMANA 1 (-1·10 kg [-1·69 to -0·40] vs -1·58 kg [-2·99 to -1·14], p=0·15) or ROMANA 2 (-1·49 kg [-2·06 to -0·58] vs -0·95 kg [-1·56 to 0·04], p=0·65). There were no differences in grade 3-4 treatment-related adverse events between study groups; the most common grade 3-4 adverse event was hyperglycaemia, occurring in one (<1%) of 320 patients given anamorelin in ROMANA 1 and in four (1%) of 330 patients given anamorelin in ROMANA 2. INTERPRETATION: Anamorelin significantly increased lean body mass, but not handgrip, strength in patients with advanced non-small-cell lung cancer. Considering the unmet medical need for safe and effective treatments for cachexia, anamorelin might be a treatment option for patients with cancer anorexia and cachexia. FUNDING: Helsinn Therapeutics.

Culture and medical decision making: Healthcare consumer perspectives in Japan and the United States.

OBJECTIVE: Two studies identified core value influences on medical decision-making processes across and within cultures. METHODS: In Study 1, Japanese and American adults reported desired levels of medical decision-making influence across conditions that varied in seriousness. Cultural antecedents (interdependence, independence, and power distance) were also measured. In Study 2, American adults reviewed a colorectal cancer screening decision aid. Decision preparedness was measured along with interdependence, independence, and desire for medical information. RESULTS: In Study 1, higher interdependence predicted stronger desire for decision-making information in both countries, but was significantly stronger in Japan. The path from information desire to decision-making influence desire was significant only in Japan. The independence path to desire for decision-making influence was significant only in the United States. Power distance effects negatively predicted desire for decision-making influence only in the United States. For Study 2, high (low) interdependents and women (men) in the United States felt that a colorectal cancer screening decision aid helped prepare them more (less) for a medical consultation. Low interdependent men were at significantly higher risk for low decision preparedness. CONCLUSIONS: Study 1 suggests that Japanese participants may tend to view medical decision-making influence as an interdependent, information sharing exchange, whereas American respondents may be more interested in power sharing that emphasizes greater independence. Study 2 demonstrates the need to assess value influences on medical decision-making processes within and across cultures and suggests that individually tailored versions of decision aids may optimize decision preparedness.

Brief versions of the FACIT-fatigue and FAACT subscales for patients with non-small cell lung cancer cachexia.

PURPOSE: Cancer anorexia-cachexia syndrome (CACS) is common in advanced cancer patients and associated with weight loss, fatigue, impaired quality of life (QoL), and poor prognosis. The goal of this project was to identify the most responsive items from two QoL measures in the ROMANA 2 (NCT01387282) phase III global study evaluating anamorelin HCl in the treatment of non-small cell lung cancer (NSCLC) cachexia: the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and the Functional Assessment of Anorexia/Cachexia Therapy (FAACT). METHODS: In the ROMANA 2 trial, 477 patients with unresectable stage III or IV NSCLC and cachexia were to be enrolled and randomized (2:1) to receive anamorelin HCl or placebo once daily for 12 weeks. All 203 patients who reached the week 12 visit at the time of data analysis were included. Co-primary endpoints were change from baseline in lean body mass and handgrip strength. QoL was a secondary outcome with FACIT-F and FAACT questionnaires administered at baseline and at weeks 3, 6, 9, and 12. RESULTS: Two 4-item scales (fatigue/activity and appetite/eating) from the FACIT-F and FAACT questionnaires, respectively, demonstrated good internal consistency reliability, validity, and responsiveness (also referred to as the Simplified Evaluation of Fatigue (SEF) and Simplified Evaluation of Appetite (SEA), respectively). The estimated important difference for each scale was 1-2 points. CONCLUSIONS: These brief scales provide the psychometric properties necessary to promote future research in NSCLC patients with CACS. Additional work should examine the clinical utility of these scales and their impact on treatment decision-making.

Anamorelin for patients with cancer cachexia: an integrated analysis of two phase 2, randomised, placebo-controlled, double-blind trials.

BACKGROUND: Cancer anorexia-cachexia syndrome is associated with increased morbidity and mortality. Anamorelin is an oral ghrelin-receptor agonist with appetite-enhancing and anabolic activity. We assessed the effects of anamorelin on body composition, strength, quality of life, biochemical markers, and safety in patients with cancer anorexia-cachexia. METHODS: Data were pooled, a priori, from two completed phase 2, multicentre, placebo-controlled, double-blind trials in patients with advanced or incurable cancer and weight loss of 5% or more. Patients were stratified by weight loss severity (5-15%, >15%) and randomly allocated (1:1) with a computer-generated randomisation schedule to anamorelin hydrochloride 50 mg or placebo once-daily for 12 weeks. Primary outcome was lean body mass by dual-energy x-ray absorptiometry over the 12 week treatment period in eligible patients who had at least one dose of study drug and post-treatment efficacy assessment. We assessed safety in all patients who received at least one dose of study drug. The trials are registered with ClinicalTrials.gov, numbers NCT00219817 and NCT00267358. FINDINGS: Between June 29, 2005, and Oct 26, 2006, we enrolled 44 patients in the anamorelin group and 38 patients in the placebo group. 74 patients were eligible for the efficacy analyses. Over 12 weeks, lean body mass increased in 38 patients in the anamorelin group by a least-squares mean of 1.89 kg (95% CI 0.84 to 2.95) compared with a decrease of a least-squares mean of -0.20 kg (-1.23 to 0.83) for 36 patients in the placebo group (difference 2.09 kg [0.94-3.25]; p=0.0006). 42 (95%) of 44 patients treated with anamorelin and 33 (87%) of 38 patients treated with placebo had adverse events. The most common grade 3-4 adverse events (treatment-related or not) in the anamorelin group were fatigue, asthenia, atrial fibrillation, and dyspnoea (two [5%] each); in the placebo group, such events were pneumonia (three [8%]) and anaemia, thrombocytopenia, abdominal pain, anxiety, and dyspnoea (two [5%] each). INTERPRETATION: Anamorelin treatment for 12 weeks had a favourable clinical response profile in patients with cancer anorexia-cachexia syndrome. These findings support further investigation in this setting. FUNDING: Helsinn Therapeutics (US), Helsinn Healthcare SA.

Cultural targeting and tailoring of shared decision making technology: a theoretical framework for improving the effectiveness of patient decision aids in culturally diverse groups.

Patient decision aids are known to positively impact outcomes critical to shared decision making (SDM), such as gist knowledge and decision preparedness. However, research on the potential improvement of these and other important outcomes through cultural targeting and tailoring of decision aids is very limited. This is the case despite extensive evidence supporting use of cultural targeting and tailoring to improve the effectiveness of health communications. Building on prominent psychological theory, we propose a two-stage framework incorporating cultural concepts into the design process for screening and treatment decision aids. The first phase recommends use of cultural constructs, such as collectivism and individualism, to differentially target patients whose cultures are known to vary on these dimensions. Decision aid targeting is operationalized through use of symbols and values that appeal to members of the given culture. Content dimensions within decision aids that appear particularly appropriate for targeting include surface level visual characteristics, language, beliefs, attitudes and values. The second phase of the framework is based on evidence that individuals vary in terms of how strongly cultural norms influence their approach to problem solving and decision making. In particular, the framework hypothesizes that differences in terms of access to cultural mindsets (e.g., access to interdependent versus independent self) can be measured up front and used to tailor decision aids. Thus, the second phase in the framework emphasizes the importance of not only targeting decision aid content, but also tailoring the information to the individual based on measurement of how strongly he/she is connected to dominant cultural mindsets. Overall, the framework provides a theory-based guide for researchers and practitioners who are interested in using cultural targeting and tailoring to develop and test decision aids that move beyond a "one-size fits all" approach and thereby, improve SDM in our multicultural world.

Shared decision making and patient decision aids: knowledge, attitudes, and practices among Hawai'i physicians.

BACKGROUND: As the health care field moves toward patient-centered care (PCC), increasing emphasis has been placed on the benefits of patient decision aids for promoting shared decision making (SDM). This study provides a baseline measure of knowledge, attitudes, and practices (KAP) among Hawai'i's physicians with respect to patient decision aids (DAs). Physicians throughout the State of Hawai'i were invited to complete a survey assessing their knowledge, attitudes, and practices with respect to the clinical use of DAs. One hundred and seventy four valid surveys were analyzed. Reported awareness and use of DAs were low, but recognition of the benefits of SDM and openness to the use of DAs were very high. The leading perceived barriers to the implementation of DAs were lack of awareness, lack of resources, and limited physician time to learn about DA technology. However, a significant majority of the respondents reported that DAs could empower patients by improving knowledge (88%), increasing satisfaction with the consultation process (81%), and increasing compliance (74%). Among physicians currently employing DAs, use of brochures or options matrix sheets was the most common aid tool. However, leading recommended DA formats were paper-based brochures for clinic use (75%) and interactive online website programs for outside clinic use (73.5%). Given growing emphasis on the PCC model and the recognized desire of many patients to participate in the medical decision making process, positive responses toward SDM and the use of DAs by Hawai'i physicians are promising.

Therapeutic potential of anamorelin, a novel, oral ghrelin mimetic, in patients with cancer-related cachexia: a multicenter, randomized, double-blind, crossover, pilot study.

PURPOSE: Cachexia in cancer adversely affects patients' perception of symptoms, well-being, and response to therapy, and shortens survival. Anamorelin, an oral mimetic of ghrelin, has been shown to increase body weight and anabolic hormone levels in healthy volunteers and is being investigated to treat cancer cachexia. METHODS: This multicenter, double-blind, placebo-controlled, crossover study evaluated the effects of anamorelin in 16 patients with different cancers and cachexia. Patients were randomly assigned to anamorelin 50 mg/day or placebo for 3 days. A 3- to 7-day washout period followed and then treatments were switched. Assessments included body weight, appetite, food intake, growth hormone (GH) levels, patient-reported symptom assessments (e.g., the Anderson Symptom Assessment Scale [ASAS] and also an inclusion criterion), and safety. RESULTS: Anamorelin significantly increased body weight compared with placebo (0.77 kg vs. -0.33 kg). Food intake increased compared with placebo, but not significantly. GH significantly increased at all time points (0.5-4 h postdose). Insulin-like growth factor-1 (IGF-1) significantly increased by 54.09 ng/mL with anamorelin treatment compared with -3.56 ng/mL for placebo; significant changes in insulin-like growth factor-binding protein 3 (IGFBP-3) were 0.75 µg/mL vs. -0.19 µg/mL, respectively. Patient-reported symptoms, including appetite as measured by ASAS, significantly improved with anamorelin (8.1 vs. 1.0 for placebo). Adverse events (AEs) in four patients were possibly or probably related to anamorelin: hyperglycemia (two patients), nausea (one patient), and dizziness (one patient). Most AEs were mild; no patients withdrew due to AEs. CONCLUSIONS: Anamorelin showed significant metabolic, clinical, and patient-rated effects in cancer cachexia. Further studies are warranted.

Impact of asking sensitive questions about violence to children and adolescents.

PURPOSE: A major gap in our understanding of the ethics of asking sensitive health questions to children is the impact these questions have on their well-being. METHODS: A survey which included sensitive questions about victimization, perpetration, and exposure to violence was fielded nationally among 1588 youth between 10 and 15 years old. At the end of the survey, youth were asked whether any questions about violence upset them. RESULTS: One in four youth (23%) indicated that they were upset by the survey questions about violence. Ten themes emerged from the youth's open-ended responses to what specifically upset them, including being upset by specific types of questions (e.g., sex, drugs), being distressed by the thought that young people were engaging in these behaviors, and finding the tone of the survey to be accusatory. Upset youth were three times more likely to be younger than non-upset youth. Victims of direct violence (e.g., physical assault) and indirect violence (e.g., witnessing violence) were no more likely to report being upset than were non-victims. CONCLUSIONS: Surveys querying sensitive topics must include younger youth to provide accurate prevalence estimates and to avoid floor effects. Great care should be taken to understand the impact that these questions have on youth and to ensure appropriate referral to support services if needed.

Phonological neighbors influence word naming through the least supported phoneme.

Recent research has shown that phonological neighborhood density facilitates naming latencies. In an attempt to extend this work, the authors evaluated the effect of phonological neighborhood distribution by comparing responding to words that consisted of 3 phonemes but differed in the number of phoneme positions that could be changed to form a neighbor (i.e., 2 vs. 3 positions). The results revealed that words in which all 3 positions could be changed to form a neighbor were named more rapidly than were words in which only 2 positions could be changed. The results show that this effect occurs due to a difference between the 2 groups of words in terms of their least supported phoneme (i.e., the phoneme position within a word with which the fewest neighbors overlap). The authors show that differences in terms of the number of neighbors for the least supported phoneme can also explain past research that indicates an effect of phonological neighborhood density on naming. The authors explain the results of this research using the dual-route cascaded model of reading aloud.

The effect of phonological neighborhood density on eye movements during reading.

Recent research has indicated that phonological neighbors speed processing in a variety of isolated word recognition tasks. Nevertheless, as these tasks do not represent how we normally read, it is not clear if phonological neighborhood has an effect on the reading of sentences for meaning. In the research reported here, we evaluated whether phonological neighborhood density influences reading of target words embedded in sentences. The eye movement data clearly revealed that phonological neighborhood facilitated reading. This was evidenced by shorter fixations for words with large neighborhoods relative to words with small neighborhoods. These results are important in indicating that phonology is a crucial component of reading and that it affects early lexical processing.