Individuals In Clinical Trials Research Articles

Genetic landscape and novel disease mechanisms from a large LGMD cohort of 4656 patients.

ObjectiveLimb‐girdle muscular dystrophies (LGMDs), one of the most heterogeneous neuromuscular disorders (NMDs), involves predominantly proximal‐muscle weakness with >30 genes associated with different subtypes. The clinical‐genetic overlap among subtypes and with other NMDs complicate disease‐subtype identification lengthening diagnostic process, increases overall costs hindering treatment/clinical‐trial recruitment. Currently seven LGMD clinical trials are active but still no gene‐therapy‐related treatment is available. Till‐date no nation‐wide large‐scale LGMD sequencing program was performed. Our objectives were to understand LGMD genetic basis, different subtypes’ relative prevalence across US and investigate underlying disease mechanisms.MethodsA total of 4656 patients with clinically suspected‐LGMD across US were recruited to conduct next‐generation sequencing (NGS)‐based gene‐panel testing during June‐2015 to June‐2017 in CLIA‐CAP‐certified Emory‐Genetics‐Laboratory. Thirty‐five LGMD‐subtypes‐associated or LGMD‐like other NMD‐associated genes were investigated. Main outcomes were diagnostic yield, gene‐variant spectrum, and LGMD subtypes’ prevalence in a large US LGMD‐suspected population.ResultsMolecular diagnosis was established in 27% (1259 cases; 95% CI, 26–29%) of the patients with major contributing genes to LGMD phenotypes being: CAPN3(17%), DYSF(16%), FKRP(9%) and ANO5(7%). We observed an increased prevalence of genetically confirmed late‐onset Pompe disease, DNAJB6‐associated LGMD subtype1E and CAPN3‐associated autosomal‐dominant LGMDs. Interestingly, we identified a high prevalence of patients with pathogenic variants in more than one LGMD gene suggesting possible synergistic heterozygosity/digenic/multigenic contribution to disease presentation/progression that needs consideration as a part of diagnostic modality.InterpretationOverall, this study has improved our understanding of the relative prevalence of different LGMD subtypes, their respective genetic etiology, and the changing paradigm of their inheritance modes and novel mechanisms that will allow for improved timely treatment, management, and enrolment of molecularly diagnosed individuals in clinical trials.

Geriatric Assessment (GA) Measures and Patient-Reported Outcomes (PROs) Among Older Adults Treated in a Phase 1b Study for Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML)

IntroductionThe measurement, analysis, and communication of treatment-related symptoms and their impact on the functioning of individuals in clinical trials is an area of interest to the medical community, the Food and Drug Administration and other regulatory agencies. Inclusion of GAs and PROs in early phase trials can characterize the heterogeneity of aging and guide development of therapies to benefit older adults. Despite evidence that GAs and PROs are feasible and predictive of outcome, few early phase trials have integrated them to inform on treatment tolerance. The aim of this analysis is to describe changes in GAs and PROs among older adults with R/R AML in a Phase 1b trial of BCL2 inhibitor venetoclax (Ven) with either MEK inhibitor cobimetinib (cobi) or MDM2 antagonist idasanutlin (idasa) (NCT02670044).MethodsPatients (pts) aged ≥60 yrs who were ineligible for cytotoxic therapy/allogeneic stem cell transplant were enrolled in this open-label, multicenter study, designed to evaluate the safety, tolerability, and efficacy of Ven+cobi/idasa in R/R or secondary AML. GA measures were Short Physical Performance Battery (SPPB; gait speed, balance tests, chair stands), Hematopoietic Cell Transplant-Comorbidity Index (HCT-CI) and Short Blessed Orientation Test (SBOT). Treatment-related symptoms were assessed via the PRO version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), administered electronically throughout treatment. GAs were administered at screening, Cycle (C) 2 Day (D) 1, C3D1, and C7D1; PRO-CTCAE was administered at C1D1, weekly during C1, for the first 3 weeks of C2 and C3, and monthly starting at C4D1. Mean GA scores were calculated over time for each treatment arm and pt-level heatmaps were created. The ‘frequency’, ‘severity’, ‘interference’, and ‘presence’ of PRO-CTCAE symptoms were reported at each assessment, with a longitudinal analysis to understand how symptoms changed over the course of treatment.ResultsAs of April 6 2018, 64 pts had been treated with either Ven+cobi or Ven+idasa. Baseline characteristics were comparable between arms; respectively: median age, 72, 74 yrs; ECOG performance status 0-1, 83%, 82%; refractory disease, 63%, 56%. GA and PRO data were available in 52 and 38 pts, respectively. Screening of GAs identified a physically frail (mean SPPB score <9), cognitively intact (mean SBOT scores <4) pt population with comorbidities (Table 1). At baseline, PRO-CTCAE showed that >70% of pts ‘never’ or ‘rarely’ experienced nausea, vomiting or diarrhea; >75% and >50% reported ‘none’ or ‘mild’ decreased appetite and fatigue, respectively. In both arms, pt numbers reduced over C1-3, with 8 pts in the Ven+cobi and 6 pts in the Ven+idasa arms providing data at C3D1; this was largely due to attrition on study. Pts reported that their worst post-baseline symptom was ‘frequent’ or ‘almost constant’ symptoms of nausea (55%), diarrhea (71%), and vomiting (5%) at some point, and ‘severe’ or ‘very severe’ decreased appetite (55%) or fatigue (55%). Variations in the worst post-baseline symptoms were observed between treatment arms, although this was not statistically tested. Symptoms tended to increase and decrease with the start and end of each treatment cycle and appeared worse during C1 for Ven+cobi (Figure 1). Despite differences in symptoms during the cycle, there did not appear to be changes in mean SPPB scores from baseline to C2, no cognitive impairment during treatment, and little to no increase in comorbidity burden. These results may be influenced by a reduction in pt numbers in each treatment arm over subsequent assessments.ConclusionPROs from this Phase 1b study indicate an increased frequency of treatment-related symptoms, in particular, nausea, diarrhea, vomiting, decreased appetite and fatigue, in older AML pts treated with Ven+cobi or Ven+idasa compared with pre-treatment. PROs and GAs can provide additional complementary insight into the older pt's treatment experience on early phase clinical trials that can inform design of later-phase studies. However, strategies to address missing data will be important for maximizing value gained. [Display omitted] DisclosuresKlepin:Genentech Inc: Consultancy. Campinha-Bacote:Genentech Inc: Employment. Hong:Genentech Inc/Roche: Employment, Other: Ownership interests PLC. Phuong:Genentech Inc: Employment, Equity Ownership, Other: Ownership interests PLC. Wang:Genentech Inc: Employment; F. Hoffmann-La Roche Ltd: Equity Ownership. Mobasher:F. Hoffmann-La Roche Ltd: Other: Ownership interests non-PLC; Genentech Inc: Employment. Trask:Genentech Inc: Employment; F. Hoffmann-La Roche: Employment.

Beta cell preservation in patients with type 1 diabetes.

The calcium channel blocker verapamil preserves beta cells in a clinical trial of individuals with adult-onset type 1 diabetes. The calcium channel blocker verapamil preserves beta cells in a clinical trial of individuals with adult-onset type I diabetes.

CV diagnosis and direct-acting antiviral agents -based treatment for HIV/HCV co-infected patients in a primary care setting in Maputo, Mozambique

Background: Direct-acting antiviral agents (DAAs) treatment has been associated with high rates of sustained virological response at week 12 after treatment completion (SVR12) and a good safety profile in HIV + /HCV + individuals in clinical trials. We aimed to assess the HCV diagnosis and DAA-based treatment feasibility in a Minister of Health (MoH) primary care setting in Maputo, Mozambique. Methods & Materials: We included for analysis the active cohort of HIV-positive adults enrolled for HIV care between March 2015-July 2017 in MSF supported MoH HIV clinic in a primary health centre in Maputo, Mozambique. Results: Among 1486 active patients enrolled between March 2015-July 2017, 1334 (90%) were screened for HCV antibodies (OraQuick HCV Rapid Antibody Test, OraSure Technologies, Bethlehem, USA): 81 (6%) patients tested antibodies positive, among them 83% had viral load (VL) detectable. GNT 1a was detected in 90% of cases, 8% were GNT 4, and 2% were GNT 3. Among patiens with HCV VL detectable, 87% were men, with a mean age of 37 years old, and 90% had a history of injectable drugs abuse. The fibrosis score by Fibroscan® was F0-F1 for 82% of patients, F2-F3 for 10%, F3-F4 for 8%. A total of 21 HIV/HCV patients were initiated on DAAs from December 2016 up to October 2017 and 15 of them completed treatment. All patients were on antiretroviral treatment at HCV treatment initiation, 35% on second line regimen (with Lopinavir/ritonavir). No severe side effects were reported. No defaulters or treatment discontinuation in this cohort. VL follow-up 12 weeks after the end of treatment was done for 4 patients: 3 patients with SVR12 achieved and one failure. Conclusion: This is the first experience of HCV treatment with DAAs in the primary care setting in public health sector in Mozambique. Injectable drugs use appears as main risk factor for HCV infection. A more comprehensive package of care with targeted testing, harm reduction interventions and treatment need to be offered to most at risk population. Inclusion of HCV routine diagnosis followed by access to treatment by new DAAs in primary HIV care setting in Maputo, mozambique, is feasible.

Unmet need for primary prevention in individuals with hypertriglyceridaemia not eligible for statin therapy according to European Society of Cardiology/European Atherosclerosis Society guidelines: a contemporary population-based study.

To identify individuals at high risk of atherosclerotic cardiovascular disease (ASCVD), who are not definite statin eligible according to the 2016 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines, based on high concentrations of plasma triglycerides. From the Copenhagen General Population Study (2003-2015) 58547 individuals aged 40-65 and free of ASCVD, diabetes, and statin use at baseline were included. Of these, 14% were definite statin eligible, 7% were not eligible and had triglycerides ≥3.0 mmol/L (264 mg/dL), and 79% were not statin eligible and had triglycerides <3.0 mmol/L (264 mg/dL). During 456057 person-years of follow-up, 1770 individuals experienced a major adverse cardiovascular event (MACE) and 734 experienced a myocardial infarction (MI). The cumulative incidences of MACE at age 70 were 8.1% (95% confidence interval 7.3-8.9%) and 14.6% (12.6-16.8%) in statin non-eligible individuals with triglycerides <3.0 mmol/L (264 mg/dL) and ≥3.0 mmol/L (264 mg/dL), and 16.5% (14.0-19.3%) in statin eligible individuals. Corresponding cumulative incidences of MI were 3.0% (2.7-3.3%), 7.8% (6.4-9.5%), and 7.1% (5.9-8.4%), respectively. The estimated 10-year risks of MACE were 2.8% (2.6-3.0%) and 5.7% (4.9-6.6%) in statin non-eligible individuals with triglycerides <3.0 mmol/L (264 mg/dL) and ≥3.0 mmol/L (264 mg/dL), and 7.6% (6.9-8.3%) in statin eligible individuals; the median age in these three groups were 51, 51, and 60 years, respectively. Corresponding risks of MI were 1.0% (0.9-1.1%), 3.0% (2.4-3.7%), and 3.3% (2.8-3.7%), respectively. Statin non-eligible individuals with triglycerides ≥3.0 mmol/L (264 mg/dL) had risk of ASCVD similar to statin eligible individuals, defined according to the 2016 ESC/EAS guidelines. This illustrates an unmet need for primary prevention, calling for expansion of guidelines on statin eligibility, and the potential for placebo-controlled randomized clinical trials in individuals with hypertriglyceridaemia.

Social cognition psychometric evaluation (SCOPE) in people with early psychosis: A preliminary study

Social cognition is an important outcome in schizophrenia research. Unfortunately, there has been a lack of consensus regarding which measures of social cognition best capture this domain of functioning. The Social Cognition Psychometric Evaluation (SCOPE) study was developed to address the need for a battery of measures that have sound psychometric properties and can be implemented in clinical trials for individuals with chronic schizophrenia. The current study expands upon the SCOPE study by examining the psychometric properties of the eight candidate measures administered to individuals early in the course of psychosis. Thirty-eight stable outpatients with first episode psychosis and thirty-nine healthy controls completed the battery at baseline and one-month follow-up assessments. The SCOPE battery was evaluated on a collection of psychometric properties, including: (1) Reliability – including test-retest and internal consistency, (2) Between group differences, (3) Utility as a repeated measure, (4) Relationship to social and occupational functioning, (5) Incremental validity – variance in functioning beyond neurocognition, and (6) Feasibility – including practicality of administration and tolerability. Social cognition accounted for substantially more variance in functional outcome than neurocognition. Only one measure, the Hinting task, displayed adequate psychometric properties to be recommended for use in clinical research with first episode psychosis. The remaining candidate measures would require modifications before implementation or cannot be recommended for use in clinical research with first episode psychosis.

A \u2018Disease Severity Index\u2019 to identify individuals with Subjective Memory Decline who will progress to mild cognitive impairment or dementia

Subjective memory decline (SMD) is a heterogeneous condition. While SMD might be the earliest sign of Alzheimer’s disease (AD), it also occurs in aging and various neurological, medical, and psychiatric conditions. Identifying those with higher risk to develop dementia is thus a major challenge. We tested a novel disease severity index generated by multivariate data analysis with numerous structural MRI measures as input. The index was used to identify SMD individuals with high risk of progression to mild cognitive impairment (MCI) or AD. A total of 69 healthy controls, 86 SMD, 45 MCI, and 38 AD patients were included. Subjects were followed up for 7.5 years. Clinical, cognitive, PET amyloid imaging and APOE ε4 data were used as outcome variables. The results showed that SMD evidenced cognitive performance intermediate between healthy controls and MCI. The disease severity index identified eleven (13%) SMD individuals with an AD-like pattern of brain atrophy. These individuals showed lower cognitive performance, increased CDR-SOB, higher amyloid burden and worse clinical progression (6.2 times higher likelihood to develop MCI, dementia or die than healthy controls). The current disease severity index may have relevance for clinical practice, as well as for selecting appropriate individuals for clinical trials.

How to define reference intervals to rule in healthy individuals for clinical trials?

How to define reference intervals to rule in healthy individuals for clinical trials?

An ECLIPSE View of Alpha-1 Antitrypsin Deficiency.

Chronic obstructive pulmonary disease (COPD) is a multicomponent condition that is estimated to become the third leading cause of death in 2020. The ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) study, funded by GlaxoSmithKline, is an observational study designed to define outcomes that can be used as endpoints in clinical trials in individuals with COPD. It allowed us to describe the heterogeneity of COPD, the stability of the exacerbation phenotype, and the factors associated with a progressive decline in lung function and the progression of emphysema on computed tomography scans. The cohort was also used to define genetic factors and biomarkers associated with COPD and disease progression. This review considers how the results from ECLIPSE can inform our understanding of the lung disease associated with alpha-1 antitrypsin deficiency.

Robust inference for mixed censored and binary response models with missing covariates

In biomedical and epidemiological studies, often outcomes obtained are of mixed discrete and continuous in nature. Furthermore, due to some technical inconvenience or else, continuous responses are censored and also a few covariates cease to be observed completely. In this paper, we develop a model to tackle these complex situations. Our methodology is developed in a more general framework and provides a full-scale robust analysis of such complex models. The proposed robust maximum likelihood estimators of the model parameters are resistant to potential outliers in the data. We discuss the asymptotic properties of the robust estimators. To avoid computational difficulties involving irreducibly high-dimensional integrals, we propose a Monte Carlo method based on the Metropolis algorithm for approximating the robust maximum likelihood estimators. We study the empirical properties of these estimators in simulations. We also illustrate the proposed robust method using clustered data on blood sugar content from a clinical trial of individuals who were investigated for diabetes.

Incidence and Patient Survival of Myeloproliferative Neoplasms (MPNs) and Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPNs) in the United States: A Population-Based View of the Modern Diagnostic Era

Introduction: Epidemiologic information on myeloproliferative neoplasms (MPNs) and myelodysplastic (MDS)/MPNs is largely derived from single institution and European population-based studies. Further, descriptive data encompassing the era of the World Health Organization classification (WHO) of hematopoietic neoplasms and JAK2 V617 mutation testing are sparse. Therefore, we utilized population-based data to comprehensively assess incidence and patient survival of MPNs and MDS/MPNs in the United States (US) during 2001-2012.Methods: Using data from the National Cancer Institute's Surveillance, Epidemiology and End Results Program (SEER) Program, we assessed the incidence rates (IRs), IR ratios (IRRs), and 95% confidence intervals (CI) for each MPN and MDS/MPN entity. We assessed IRs overall and according to sex, race/ethnicity, calendar year of diagnosis, and method of diagnostic confirmation. We utilized the SEER*Stat Survival Session to calculate 5-year relative survival (RS) and 95% CI for each disease entity overall and according to sex and age at diagnosis.Results: A total of 44,912 patients were diagnosed with MPNs and MDS/MPNs during 2001-2012. IRs were highest for polycythemia vera (PV) (n=10,812; IR=10.9 per 1,000,000 person-years) and essential thrombocythemia (ET) (n=9,394; IR=9.6). Except for ET and mastocytosis, the overall IRs for all entities were significantly higher among males than females, with male-to-female IRRs ranging from 1.4-2.3. PV incidence peaked in 2003-2004 and progressively decreased thereafter in contrast to IRs for ET which markedly increased after 2003-2004, with a suggestion of decrease after 2008. BCR-ABL1-positive chronic myelogenous leukemia (CML) IRs increased progressively over the study period while CML, NOS decreased over the study decade. All evaluable MPNs were associated with lower IRs among Hispanic whites than non-Hispanic whites (NHWs), with the exception of BCR-ABL1-positive CML, chronic eosinophilic leukemia (CEL), and juvenile myelomonocytic leukemia which occurred similarly among both groups. Except for CEL, Asians/Pacific Islanders had significantly lower MPN IRs than NHWs. ET, MPN-unclassifiable, and CEL IRs were 18%, 19%, and 60% higher, respectively, among blacks than NHWs. Among males and females, for all evaluable MPNs and MDS/MPNs, five-year RS was more favorable for younger (<60 years) than older (>60 years) individuals. Patients with PV or ET had the most favorable RS among both sexes and age groups, ranging from 92.0%-96.7% among those <60 years and 79.1%-87.9% among those >60 years. Patients with chronic neutrophilic leukemia, chronic myelomonocytic leukemia, and atypical BCR-ABL1 -negative CML patients had the least favorable 5-year RS (<35%). Females generally had more favorable survival than males, except for older males with PV who had significantly better survival than older women (RS IRR=1.08, 95%CI=1.03-1.13).Conclusion: MPNs are a heterogeneous group of diseases and varying age, sex, and racial/ethnic incidence patterns support distinct etiologies and/or susceptible populations. The introduction of JAK2 V617 mutation testing in 2005 may have had a differential impact on IRs of PV and ET. Less favorable RS among older ages for all MPN subtypes suggests the need for inclusion of these individuals in clinical trials as new treatments become available. DisclosuresNo relevant conflicts of interest to declare.

Effect of pitavastatin on glucose, HbA1c and incident diabetes: A meta-analysis of randomized controlled clinical trials in individuals without diabetes.

Whether adverse effect of statins on glycaemic indices is common to all statins remains controversial and as yet data for pitavastatin are limited. We sought to assess the effects of pitavastatin on glycaemia and new-onset diabetes (NOD) in non-diabetic individuals using data from RCT pooled together by means of a meta-analysis. We searched Medline, Cochrane, Embase and clinical trials registries websites until November-2014 for ≥12-week follow-up placebo or statin-controlled RCT of pitavastatin that included participants without diabetes and reported on fasting blood glucose (FBG), HbA1c or NOD. We additionally sought studies by consulting with Kowa Ph. Ltd. The association of pitavastatin with the outcomes were estimated by random-effects meta-analyses. Heterogeneity was assessed by the I(2) statistic and sensitivity and subgroup analyses, and publication bias with funnel plots and Egger and Harbord Tests. 15 studies (approx. 1600 person-years) were included. No significant differences associated with pitavastatin (vs. control) were observed for FBG (MD-0.01mg/dL [95%CI-0.77, 0.74], I(2)=0%), HbA1c (MD-0.03% [95%CI-0.11, 0.05], I(2)=43%) or NOD (RR 0.70 [95%CI 0.30, 1.61]; RD 0.0 [95%CI-0.004, 0.003]; I(2)=0%). Sensitivity and subgroup analyses (including type of control [placebo or other statin], pitavastatin dose or follow-up] did not yield significant results. Potential publication bias may occur for NOD. In the present meta-analysis pitavastatin did not adversely affect glucose metabolism or diabetes development compared with placebo or other statins.

Rett Syndrome: Reaching for Clinical Trials.

Rett syndrome (RTT) is a syndromic autism spectrum disorder caused by loss-of-function mutations in MECP2. The methyl CpG binding protein 2 binds methylcytosine and 5-hydroxymethycytosine at CpG sites in promoter regions of target genes, controlling their transcription by recruiting co-repressors and co-activators. Several preclinical studies in mouse models have identified rational molecular targets for drug therapies aimed at correcting the underlying neural dysfunction. These targeted therapies are increasingly translating into human clinical trials. In this review, we present an overview of RTT and describe the current state of preclinical studies in methyl CpG binding protein 2-based mouse models, as well as current clinical trials in individuals with RTT.

Optimal targets for blood pressure control in chronic kidney disease: the debate continues.

Because advanced chronic kidney disease (CKD) is often an exclusion criterion for large randomized trials of the management of hypertension, clinical decision making for these patients has relied on a few small, specific studies and much extrapolation. Several blood pressure treatment guidelines have recently been reissued. This review explores the applicability of the revised recommendations to CKD. Many new publications are meta-analyses, guidelines and debates about guidelines. New data from trials are scant. Three revised guidelines (KDIGO, JNC8, KHA-CARI) recommend a target of less than 140/90. Most antihypertensive drugs are equally effective - but this rule may not apply to advanced CKD. Proteinuric renal disease is seen as an exception; all three guidelines set a target of 130/80 and the use of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (but not both) is preferred. There is no shortage of new commentary and advice, but evidence strength and generalizability diminish as the kidneys fail and the impact of calcified vessels and salt and water overload increases. A risk-based approach to intervention may be no less valuable than targets. Clinical trials of individuals with advanced CKD will be needed to identify effective treatments and may see a resurgence of the role of spironolactone.

Improving our messages about research participation: a community-engaged approach to increasing clinical trial literacy

We are all aware that recruiting individuals for clinical trials (CTs) is not an easy task and it can be even more challenging to recruit within underserved populations. Numerous barriers to participation have been reported including individuals’ limited awareness and knowledge about CTs, misperceptions and fear of research and distrust of doctors and researchers [1–4]. We argue in this report that the way we as researchers and scientists communicate about CTs and research participation in general is also a significant barrier to recruitment, enrollment and participation [5]. There is tremendous potential to improve our messaging about research, which, in turn, can improve the ‘clinical trial literacy’ of those most in need of these studies and whose participation could help advance science. Providers tend to overestimate patients’ health literacy skills and the clarity of their own communication [6]. Results from the 2012 Program for the International Assessment of Adult Competencies, for example, demonstrated that the US average literacy score was 270 or at Level 2 (Level 5 or scores between 376 and 500 demonstrate highest proficiency) [7]. Respondents who self-reported ‘poor’ health often scored at or below Level 1 in literacy (38%), numeracy (52%) and problem solving (81%). Poor health-related literacy is associated with negative health outcomes [8]. Use of jargon-free language (at a ∼Grade 5–6 level) is strongly recommended for all healthrelated content [8,9]. At the national level, the US President signed the Plain Writing Act into law in 2010 requiring federal agencies to use ‘communication that the public can understand and use’ [10]. So why not apply principles of plain language communication to our messages about research participation? In this paper, we present our approach to researching CT communication needs and message strategies. We encourage other teams to consider similar methods to guide their CT messaging.

Longitudinal trajectories of aberrant behavior in fragile X syndrome.

The Aberrant Behavior Checklist-Community (ABC-C; Aman et al., 1995) has been increasingly adopted as a primary tool for measuring behavioral change in clinical trials for individuals with fragile X syndrome (FXS). To our knowledge, however, no study has documented the longitudinal trajectory of aberrant behaviors in individuals with FXS using the ABC-C. As part of a larger longitudinal study, we examined scores obtained on the ABC-C subscales for 124 children and adolescents (64 males, 60 females) with FXS who had two or more assessments (average interval between assessments was approximately 4 years). Concomitant changes in age-equivalent scores on the Vineland Adaptive Behavior Scales (VABS) were also examined. As expected for an X-linked genetic disorder, males with FXS obtained significantly higher scores on all subscales of the ABC-C and significantly lower age-equivalent scores on the VABS than females with FXS. In both males and females with FXS, scores on the Irritability/Agitation and Hyperactivity/Noncompliance subscales of the ABC-C decreased significantly with age, with little to no change occurring over time on the Lethargy/Social Withdrawal, Stereotypic Behavior, and Inappropriate Speech subscales. The decrease in scores on the Hyperactivity/Noncompliance domain was significantly greater for males than for females. In both males and females, age-equivalent scores on the VABS increased significantly over this developmental period. These results establish a basis upon which to evaluate long-term outcomes from intervention-based research. However, longitudinal direct observational studies are needed to establish whether the severity of problem behavior actually decreases over time in this population.

Systemic Treatment of Older Patients with Advanced Breast Cancer

Due to its increasing incidence and longer life expectancy, more patients are being diagnosed with breast cancer at older ages. There are very limited data on the optimum management of older patients with advanced breast cancer, due to the under-representation of such individuals in clinical trials. Although older patients have more indolent disease with more Hormone Receptor positive disease and less HER2-positive disease, their disease-specific mortality remains lower than in younger patients, owing to the late diagnosis, under treatment due to age bias, reduced access to healthcare, and socioeconomic issues. Older patients with advanced breast cancer should be treated based on their biological tumor type, according to the patient’s general health and preferences: endocrine treatment for HR-positive disease; Human Epidermal Growth Factor Receptor 2-targeted agent with chemotherapy, endocrine therapy or HER2-targeted agent alone for HER2 positive disease. Chemotherapy should be considered for patients who are HR-negative, HR-positive but refractory to endocrine treatment, or with a rapidly progressing visceral crisis. Generally, sequential chemotherapy with a single agent is recommended over combination chemotherapy, and agents with known toxicities in older patients are recommended, including weekly taxane, vinorelbine, capecitabine, and liposomal doxorubicin. Some form of geriatric assessment should be performed for older patients to assess the patients’ biological age, functional status, and address age-specific problems, leading to early interventions. The goal of therapy should be individualized to maintain the quality of life, function, and independence of older patients with cancer. (Korean J Med 2014;87:542-547)

Dissociations in the meaning of risk between health-care professionals and individuals with spinal cord injury

Risks have been a central concern in stem cell research overall, and in clinical trials of individuals with spinal cord injury (ISCIs) in particular. We sought to elucidate how two important stakeholder groups-health-care professionals (HCPs) and ISCIs-view and value both the physical and non-physical risks of stem cell interventions. The study was conducted in Canada, and included participants from both Canada and the United States America. We used semi-structured interviews to gain perspectives on risk from HCPs and ISCIs. We applied a constant comparative analytic strategy to derive themes from the discourse collected through the interviews. We identified three major themes about risk from 12 HCP and 24 ISCI participants: focus, rationale and approach. The salient components of the themes differed: HCPs focus on the physical causes of risks, and the ISCIs on their downstream consequences as well as on non-physical risks; HCPs are concerned about evidence, and ISCIs about experience; and HCPs approach risk narrowly, whereas the approach of ISCIs is more broad and contextualized. Although major themes were common to the two stakeholder groups, the components of the themes were dissociable and illustrate differences in what HCPs and ISCIs worry about, why they worry and how they approach their worries. We draw upon these findings to make recommendations for improving risk communication and informed consent for stem cell research for spinal cord injury.

Advances in the treatment of neurofibromatosis-associated tumours

Neurofibromatosis (NF) comprises two distinct genetic disorders-neurofibromatosis type 1 and 2 (NF1 and NF2)-in which affected individuals develop both benign and malignant tumours. NF1 results from germline mutations in the NF1 gene that encodes neurofibromin, while NF2 results from germline mutations in the NF2 gene that encodes merlin (or schwannomin). The major tumour types arising in individuals with NF1 include neurofibromas, malignant peripheral nerve sheath tumours, and gliomas, whereas NF2 is characterized by the formation of schwannomas, meningiomas, and ependymomas. With the identification of the NF1 and NF2 genes and the generation of robust preclinical mouse models of NF-associated neoplasms, novel treatments that specifically target the growth control pathways deregulated in these tumours have been discovered, some of which are now being tested in clinical trials in individuals with NF1 and NF2. In this Review, we will highlight the key clinical features of NF1 and NF2 and the advances in future clinical management based on an improved understanding of the function of the NF1 and NF2 genes and the development of small-animal models.

Hypoglycemia as a Driver of Cardiovascular Risk in Diabetes

Severe hypoglycemia in patients with diabetes is associated with increased risk of adverse cardiovascular events and death. Recent large randomized clinical trials in individuals with type 2 diabetes have shown that intensive glycemic control may result in increased mortality, and hypoglycemia has been investigated as a possible cause. Acute hypoglycemia is a proarrhythmic, proinflammatory, and prothrombotic state, and several mechanisms have been proposed to explain how hypoglycemia might increase cardiovascular morbidity and mortality. However, data from large clinical trials do not provide strong evidence to establish hypoglycemia as a cause of increased mortality. Severe hypoglycemia is also a marker of frailty and a predictor of adverse outcomes in patients with diabetes. Individualized therapy should be the goal in patients with diabetes to avoid severe hypoglycemia and any related adverse outcomes.