bluuebunny/crossref_metadata_2025 huggingface dataset:
Bayesian models for subgroup analysis in clinical trials
Authors: Jones Hayley E , Ohlssen David I , Neuenschwander Beat , Racine Amy , Branson Michael
Published: February 2011

Background In a pharmaceutical drug development setting, possible interactions between the treatment and particular baseline clinical or demographic factors are often of interest. However, the subgroup analysis required to investigate such associations remains controversial. Concerns with classical hypothesis testing approaches to the problem include low power, multiple testing, and the possibility of data dredging.

Purpose As an alternative to hypothesis testing, the use of shrinkage estimation techniques is investigated in the context of an exploratory post hoc subgroup analysis. A range of models that have been suggested in the literature are reviewed. Building on this, we explore a general modeling strategy, considering various options for shrinkage of effect estimates. This is applied to a case-study, in which evidence was available from seven-phase II–III clinical trials examining a novel therapy, and also to two artificial datasets with the same structure.

Methods Emphasis is placed on hierarchical modeling techniques, adopted within a Bayesian framework using freely available software. A range of possible subgroup model structures are applied, each incorporating shrinkage estimation techniques.

Results The investigation of the case-study showed little evidence of subgroup effects. Because inferences appeared to be consistent across a range of well-supported models, and model diagnostic checks showed no obvious problems, it seemed this conclusion was robust. It is reassuring that the structured shrinkage techniques appeared to work well in a situation where deeper inspection of the data suggested little evidence of subgroup effects.

Limitations The post hoc examination of subgroups should be seen as an exploratory analysis, used to help make better informed decisions regarding potential future studies examining specific subgroups. To a certain extent, the degree of understanding provided by such assessments will be limited by the quality and quantity of available data.

Conclusions In light of recent interest by health authorities into the use of subgroup analysis in the context of drug development, it appears that Bayesian approaches involving shrinkage techniques could play an important role in this area. Hopefully, the developments outlined here provide useful methodology for tackling such a problem, in-turn leading to better informed decisions regarding subgroups.
Educational Marketing: A Review and Implications for Supporting Practice in Tertiary Education
Authors: Stachowski Christopher Allen
Published: February 2011

This article reviews the existing educational marketing literature in the leading tertiary educational management journals. A discussion of the implications for supporting practitioners in non-university settings is presented.
Emotional Intelligence: A Study of Female Secondary School Headteachers
Authors: Cliffe Joanne
Published: February 2011

The notion that emotional intelligence can be correlated with work success is well documented, particularly with regard to leadership in the business world. However, there are few empirical studies which detail the interplay of intelligent use of emotions in school leadership. This article explores the relationship between emotional intelligence and educational leadership by drawing on the responses of seven female secondary school headteachers to emotional intelligence domains as defined by Goleman (1995). While ‘positive’ correlations were found, notably that these headteachers had been able to, knowingly or subconsciously, make intelligent use of their emotions; the issue of ‘negative’ aspects or the ‘dark side’ of emotional intelligence is considered.
Educational Problems and Solutions in Turkey: The Views of District Governors
Authors: Erdem Mustafa , Aydin Inayet , Tasdan Murat , Akin Ugur
Published: February 2011

The main purpose of this article is to assess the opinions of district governors, who are the highest ranked civilian authority within a district, on educational problems and solutions at the local level. A qualitative research approach was utilized. The district governors believe that they have a very significant and active role in raising standards of education in Turkey. The findings show that district governors spend a considerable amount of time on education-related issues. The district governors asserted that central government should simply determine the general policies concerning education and provide them with more authority.
Understanding Principal Leadership: An International Perspective and a Narrative Approach
Authors: Slater Charles L.
Published: February 2011

This article reviews recent literature in educational administration that supports the argument that leadership matters. School principals exert influence on teachers, who in turn affect student achievement. There is a need for an international approach both to replicate large studies and to use a narrative approach to study leaders in their historical and school context. Concepts and methods from adult development can provide an understanding of the role of the principal. Future research in educational administration should address the lives of principals expressed in their own voices.
Worlds, Fields and Networks: Becker, Bourdieu and the Structures of Social Relations
Authors: Bottero Wendy , Crossley Nick
Published: February 2011

This paper reflects upon Bourdieu’s concept of cultural fields, Becker’s concept of ‘art worlds’ and the concept of networks as developed in social network analysis. We challenge the distinction that Bourdieu makes between the objective ‘relations’ and ‘positions’ constitutive of ‘social space’ and visible social relationships. In contrast, we maintain that interaction is generative of social spaces and positions and should be integral to any account of them. Becker’s position is better from this perspective, but while Becker refers repeatedly to social networks, he fails to develop the concept or exploit its potential as a means of exploring social structures. Both Becker and Bourdieu have an underdeveloped conception of social connection which weakens their respective conceptions of the space of cultural production. Our proposed remedy is to use social network analysis to derive ‘positions’ and ‘relations’ between ‘positions’, as prioritized by Bourdieu, from data on concrete interactions and relations. This allows ‘world’ analysis to speak to the issues of field analysis without sacrificing its strengths. We illustrate our case by way of an analysis of two UK music scenes from the late 1970s.
The effects of growth and differentiation factor 5 on bone marrow stromal cell transplants in an in vitro tendon healing model
Authors: Hayashi M. , Zhao C. , An K.-N. , Amadio P. C.
Published: February 2011

The effects of growth differentiation factor-5 (GDF-5) and bone marrow stromal cells (BMSCs) on tendon healing were investigated under in vitro tissue culture conditions. BMSCs and GDF-5 placed in a collagen gel were interpositioned between the cut ends of dog flexor digitorum profundus tendons. The tendons were randomly assigned into four groups: 1) repaired tendon without gel; 2) repaired tendon with BMSC-seeded gel; 3) repaired tendon with GDF-5 gel without cells; and 4) repaired tendon with GDF-5 treated BMSC-seeded gel. At 2 and 4 weeks, the maximal strength of repaired tendons with GDF-5 treated BMSCs-seeded gel was significantly higher than in tendons without gel interposition. However, neither BMSCs nor GDF-5 alone significantly increased the maximal strength of healing tendons at 2 or 4 weeks. These results suggest that the combination of BMSCs and GDF-5 accelerates tendon healing, but either BMSCs or GDF-5 alone are not effective in this model.
Kirschner wire fixation for scaphoid fractures: an experimental study in synthetic bones
Authors: Gokce V. , Oflaz H. , Dulgeroglu A. , Bora A. , Gunal I.
Published: February 2011

We have studied the biomechanical stability in vitro of three different Kirschner (K) wire configurations in three types of simulated scaphoid waist fractures. The fractures were created with a saw in Sawbones models. There were three fracture patterns: perpendicular to the long axis of the scaphoid model; and 30° and 20° oblique to that. Two 1.2 mm. K-wires were used in each scaphoid. The three configurations were: parallel; 20° oblique; and crossing. The oblique or crossing configurations of K-wires were the most stable depending on the fracture pattern.
Primary cup fixation with different designs of trapeziometacarpal total joint trapezium components: a radiostereometric analysis in a pig bone model
Authors: Hansen T. B. , Meier M. , Møller M. C. M. , Larsen K. , Stilling M.
Published: February 2011

High loosening rates of the trapezium components of trapeziometacarpal total joint prostheses have been reported. The purpose of this study was to compare the primary press fit fixation of two different, uncemented cup designs (MOTEC and Elektra) with the primary fixation of a cemented polyethylene cup (DLC) in a pig bone model. We did a push out test to measure the maximal load strength of the implants and a low-pressure cyclic loading test combined with radiostereometric analysis to measure the micromotion of the implants. There was no significant difference in fixation strength between the two uncemented screw cup designs or between the two uncemented screw cups and the cemented polyethylene cup. However, we found that threading of the bone before insertion of the Electra screw cup weakens the primary fixation strength of the implant. The results indicate that focus should be on the insertion technique as well as on the cup design of uncemented trapezium cup implants. Further studies of trapezium implant migration in a clinical setting are needed.
A new plate for partial wrist fusions: results in midcarpal arthrodesis
Authors: Allison D. M.
Published: February 2011

Partial wrist fusions are commonly performed for various degenerative conditions. In this series 30 wrists had a scaphoidectomy and midcarpal arthrodesis performed with a new plate. The most common indications were SLAC and SNAC wrists. In 24 cases a four-corner arthrodesis was done and in the other six the triquetrum was not included. Mean follow-up was 3 years. Mean flexion was 31° and extension 35°. Union was achieved in all wrists despite movement being commenced early. The plates proved straightforward to use, allowing some latitude in placement. This series confirms that scaphoidectomy and midcarpal arthrodesis is a useful salvage procedure and that these plates are suitable for that purpose.
Long term results of early active extension and passive flexion mobilization following one-stage tendon grafting for neglected injuries of the flexor digitorum profundus in children
Authors: Yamazaki Hiroshi , Kato Hiroyuki , Uchiyama Shigeharu , Iwasaki Norimasa , Ishikura Hisamitsu , Minami Akio
Published: February 2011

We retrospectively reviewed the long-term clinical outcomes of one-stage flexor tendon grafting for seven paediatric patients with isolated flexor digitorum profundus (FDP) tendon injuries in Zones 1 or 2. Free tendon grafts (one palmaris longus tendons and six plantaris tendons) were used for reconstruction by Pulvertaft’s procedure. The ages of the patients at reconstruction ranged from 7 to 15 (mean 11) years. The time from injury to surgery ranged from three to 78 (mean 25) months. These patients were followed up from 2.5 to 21 years after surgery (mean 8.5 years). All cases were started on early active extension and passive flexion according to the modified Kleinert mobilization for postoperative rehabilitation. The mean active motion after surgery was 49° (range 20–80°) for the DIP joints and 106° (range 95–110°) for the PIP joints. The total active range of motion was on average 237° (range 195–275°). Excellent results were achieved in five patients, good in one, and fair in one. Growth arrest of the distal phalanx was seen in one patient. One-stage flexor tendon grafting in paediatric patients combined with early controlled mobilization can be used to reconstruct neglected isolated ruptures of the FDP tendon with satisfactory results.
The tension band principle and angular testing of extensor tendon repairs
Authors: Henderson J. , Sutcliffe M. , Gillespie P.
Published: February 2011

Extensor tendons in the finger are flat and not amenable to repair by core and epitendinous sutures. Mattress sutures and Kessler repairs without epitendinous stitching are often used for extensor tendon divisions in the fingers. Except when in full extension, the finger presents a series of curved surfaces (at each joint) to the tendon. It was hypothesized that extensor tendons are subject to the ‘tension band’ principle and that they might be amenable to repair by dorsal-only epitendinous sutures. A Silfverskiöld dorsal-only repair was compared with mattress and Kessler repairs in vitro on a curvilinear testing apparatus. The epitendinous technique was found to be significantly more resistant to gapping and rupture, as well as more resistant to deformation (i.e. stiffer) than the conventional techniques.
The outcome of wrist surgery: what factors are important and how should they be reported?
Authors: Birch A. , Nuttall D. , Stanley J. K. , Trail I. A.
Published: February 2011

A prospective longitudinal study was carried out on a cohort of 86 patients who had undergone surgery for diverse wrist conditions. Disabilities of Arm Shoulder and Hand questionnaire, a pain assessment, a wrist functional score, range of movement and grip strength measures were completed. The Mayo Clinic wrist score was also calculated. The World Health Organization International Classification of Function was used as a framework for analysis. The responsiveness of each outcome measure was calculated in terms of distribution- and anchor-based methods. Pain was the most important factor in determining outcome. Changes in objective measures were less important. The responsiveness of the various measures was similar except for the Mayo Clinic wrist score, which was less responsive than the others. Patient-completed measures currently in use are multidimensional. Classifying the content according to the International Classification of Function would clarify the effects of wrist surgery on the different aspects of health.
Which instrument should we use to assess hand function after digital replantation?
Authors: Kamburoğlu H. O. , Aksu A. E. , Sönmez E. , İşçi E. T. , Şafak T. , Keçik A.
Published: February 2011

The functional recovery of a replanted body part is as important as its viability. We compared four instruments frequently used for the evaluation of hand function after digital replantation. The functional results of 17 patients at least one year after replantation of a total digital amputation between 2004 and 2007 were evaluated according to the Tamai, Ipsen, Chen and Disabilities of the Arm, Shoulder and Hand questionnaires. Scores of each patient for each test were calculated and intra-individual comparisons were made. Correlation was significant at the 0.05 level (two tailed) for all tests. A high correlation (>0.71) was found between the Ipsen, Tamai and DASH tests. The Chen test had a moderate correlation with the other tests. We determined that Ipsen, Tamai and DASH tests have similar effectiveness in assessing hand function after replantation.
Impact of inspiratory muscle training in patients with COPD: what is the evidence?
Authors: Gosselink R. , De Vos J. , van den Heuvel S.P. , Segers J. , Decramer M. , Kwakkel G.
Published: February 2011

A meta-analysis including 32 randomised controlled trials on the effects of inspiratory muscle training (IMT) in chronic obstructive pulmonary disease (COPD) patients was performed. Overall and subgroup analyses with respect to training modality (strength or endurance training, added to general exercise training) and patient characteristics were performed. Significant improvements were found in maximal inspiratory muscle strength (PI,max; +13 cmH2O), endurance time (+261 s), 6- or 12-min walking distance (+32 and +85 m respectively) and quality of life (+3.8 units). Dyspnoea was significantly reduced (Borg score -0.9 point; Transitional Dyspnoea Index +2.8 units). Endurance exercise capacity tended to improve, while no effects on maximal exercise capacity were found. Respiratory muscle endurance training revealed no significant effect onPI,max, functional exercise capacity and dyspnoea. IMT added to a general exercise programme improvedPI,maxsignificantly, while functional exercise capacity tended to increase in patients with inspiratory muscle weakness (PI,max<60 cmH2O).

IMT improves inspiratory muscle strength and endurance, functional exercise capacity, dyspnoea and quality of life. Inspiratory muscle endurance training was shown to be less effective than respiratory muscle strength training. In patients with inspiratory muscle weakness, the addition of IMT to a general exercise training program improvedPI,maxand tended to improve exercise performance.
Circulating endothelial progenitor cells and chronic pulmonary diseases
Authors: Huertas A. , Palange P.
Published: February 2011

Circulating endothelial progenitor cells (EPCs) are bone marrow-derived cells that contribute to vascular healing and remodelling under physiological and pathological conditions. Although controversies exist regarding the definition and origin of EPCs, it has been widely demonstrated that they are involved in several diseases and that they have therapeutic implications.

Chronic obstructive pulmonary disease (COPD) is characterised by airflow limitation that is not fully reversible, associated with abnormalities of airways (bronchitis) and parenchyma (emphysema), reduced exercise tolerance and systemic inflammation.

Growing evidence has also suggested that endothelial dysfunction may play a role in COPD. Although it is not clear whether endothelial dysfunction represents a cause or a consequence of COPD, several studies have highlighted the importance of EPCs in this disease, suggesting that the bone marrow could be a novel target of COPD.

The present review summarises the role of EPCs in pulmonary diseases, with particular emphasis on COPD. The aim is to improve understanding as to the possible role of EPCs in COPD pathophysiology. This may help in the identification of novel diagnostic and therapeutic tools in COPD.
Blockade of Th1 chemokine receptors ameliorates pulmonary granulomatosis in mice
Authors: Kishi J. , Nishioka Y. , Kuwahara T. , Kakiuchi S. , Azuma M. , Aono Y. , Makino H. , Kinoshita K. , Kishi M. , Batmunkh R. , Uehara H. , Izumi K. , Sone S.
Published: February 2011

Sarcoidosis is a granulomatous disease of unknown aetiology. We identified immunological targets for the treatment of pulmonary granulomatosis using a murine model generated withPropionibacterium acnes.

Sensitisation and challenge using heat-killedP. acnesand dendritic cells (DCs) were performed to produce pulmonary granulomatosis in C57BL/6 mice. Immunological analyses using ELISA as well as cDNA microarray analysis were used to search for cytokines or chemokines associated with the formation of granulomas in the lungs.

Co-administration ofP. acnesand DCs reproducibly induced the formation of pulmonary granulomas, which resembled sarcoid granulomas. The cDNA microarray assay demonstrated that the gene expression of CXCL9 and CXCL10, ligands for CXCR3, and of CCL4, a ligand for CCR5, was strongly upregulated during granulomatosis. ELISA confirmed that levels of CXCL9 and CXCL10 as well as T-helper (Th)1 cytokines and chemokines including tumour necrosis factor-α and interferon-γ were elevated in bronchoalveolar lavage fluid (BALF). The blockade of Th1 chemokine receptors using TAK-779, a dual blocker for CXCR3 and CCR5, led to reduced numbers of CXCR3+CD4+ and CCR5+CD4+ T-cells in BALF. Furthermore, administration of TAK-779 ameliorated the granulomatosis.

The targeted inhibition of Th1 chemokines might be useful for inhibiting Th1-biased granulomatous diseases, including sarcoidosis.
The Movement for Global Mental Health
Authors: Patel Vikram , Collins Pamela Y. , Copeland John , Kakuma Ritsuko , Katontoka Sylvester , Lamichhane Jagannath , Naik Smita , Skeen Sarah
Published: February 2011

The Movement for Global Mental Health is a coalition of individuals and institutions committed to collective actions that aim to close the treatment gap for people living with mental disorders worldwide, based on two fundamental principles: evidence on effective treatments and the human rights of people with mental disorders.
Quantifying the effect of early retirement on the wealth of individuals with depression or other mental illness
Authors: Schofield Deborah J. , Shrestha Rupendra N. , Percival Richard , Kelly Simon J. , Passey Megan E. , Callander Emily J.
Published: February 2011

Background

In addition to the health burden caused by mental illnesses, these conditions contribute to economic disadvantage because of their impact on labour force participation.

Aims

To quantify the cost of lost savings and wealth to Australians aged 45–64 who retire from the labour force early because of depression or other mental illness.

Method

Cross-sectional analysis of the base population of Health&WealthMOD, a microsimulation model built on data from the Australian Bureau of Statistics' Survey of Disability, Ageing and Carers and STINMOD, an income and savings microsimulation model.

Results

People who are not part of the labour force because of depression or other mental illness have 78% (95% CI 92.2–37.1) and 93% (95% CI 98.4–70.5) less wealth accumulated respectively, compared with people of the same age, gender and education who are in the labour force with no chronic health condition. People who are out of the labour force as a result of depression or other mental illness are also more likely to have the wealth that they do have in cash assets, rather than higher-growth assets such as superannuation, home equity and other financial investments.

Conclusions

This lower accumulated wealth is likely to result in lower living standards for these individuals in the future. This will compound the impact of their condition on their health and quality of life, and put a large financial burden on the state as a result of the need to provide financial assistance for these individuals.
Overcrowding in psychiatric wards and physical assaults on
staff: data-linked longitudinal study
Authors: Virtanen Marianna , Vahtera Jussi , Batty G. David , Tuisku Katinka , Pentti Jaana , Oksanen Tuula , Salo Paula , Ahola Kirsi , Kivimäki Mika
Published: February 2011

Background

Patient overcrowding and violent assaults by patients are two major
problems in psychiatric healthcare. However, evidence of an association
between overcrowding and aggressive behaviour among patients is mixed and
limited to small-scale studies.

Aims

This study examined the association between ward overcrowding and violent
physical assaults in acute-care psychiatric in-patient hospital
wards.

Method

Longitudinal study using ward-level monthly records of bed occupancy and
staff reports of the timing of violent acts during a 5-month period in 90
in-patient wards in 13 acute psychiatric hospitals in Finland. In total
1098 employees (physicians, ward head nurses, registered nurses, licensed
practical nurses) participated in the study. The outcome measure was
staff reports of the timing of physical assaults on both themselves and
ward property.

Results

We found that 46% of hospital staff were working in overcrowded wards, as
indicated by >10 percentage units of excess bed occupancy, whereas
only 30% of hospital personnel were working in a ward with no excess
occupancy. An excess bed occupancy rate of >10 percentage units at the
time of an event was associated with violent assaults towards employees
(odds ratio (OR) = 1.72, 95% CI 1.05–2.80; OR = 3.04, 95% CI 1.51–6.13 in
adult wards) after adjustment for confounding factors. No association was
found with assaults on ward property (OR = 1.06, 95% CI 0.75–1.50).

Conclusions

These findings suggest that patient overcrowding is highly prevalent in
psychiatric hospitals and, importantly, may increase the risk of violence
directed at staff.
Life stress, 5-HTTLPR and mental disorder: findings from a 30-year longitudinal study
Authors: Fergusson David M. , Horwood L. John , Miller Allison L. , Kennedy Martin A.
Published: February 2011

Background

Recent meta-analyses have raised concerns about the replicability of gene × environment interactions involving the serotonin transporter gene (5-HTTLPR) in moderating the associations between adverse life events and mental disorders.

Aims

To use data gathered over the course of a 30-year longitudinal study of a New Zealand birth cohort to test the hypothesis that the presence of short (‘s’) alleles of 5-HTTLPR are associated with an increased response to life stress.

Method

Participants were 893 individuals from the Christchurch Health and Development Study who had complete data on: the 5-HTTLPR genotype; psychiatric disorders up to the age of 30; and exposure to childhood and adult adverse life events.

Results

A series of 104 regression models were fitted to four mental health outcomes (depressive symptoms, major depression, anxiety disorder and suicidal ideation) observed at ages 18, 21, 25 and 30 using 13 measures of life-course stress that spanned childhood and adult stressors. Both multiplicative and additive models were fitted to the data. No evidence was found that would support the hypothesis that ‘s' alleles of 5-HTTLPR are associated with increased responsivity to life stressors.

Conclusions

The present findings add to the evidence suggesting that it is unlikely that there is a stable gene × environment interaction involving 5-HTTLPR, life stress and mental disorders.
Patients repeatedly attending accident and emergency departments seeking psychiatric care
Authors: Okorie Eugene F. , McDonald Colm , Dineen Brendan
Published: February 2011

Aims and method

This study was conducted to ascertain the clinical characteristics of patients who repeatedly attend accident and emergency (A&E) department seeking psychiatric assessment and care. We identified 24 individuals who attended frequently and compared them with 72 matched single attenders using data abstracted by chart review.

Results

Individuals who attended frequently made up 5.3% of all patients who attended the A&E department for psychiatric care but accounted for 19% of all such presentations. Compared with controls, they were younger at first psychiatric contact and had higher rates of schizophrenia and psychiatric admissions.

Clinical implications

A small but distinctive group of patients repeatedly seek and obtain hospital-based psychiatric care. Early identification of these patients and targeting them with effective, community-oriented strategies, such as home treatment, could improve their quality of life and prognoses as well as reduce the cost of their care.
Improving physical health monitoring in secondary care for patients on clozapine
Authors: Bolton Philipp J.
Published: February 2011

Aims and method

To assess how well psychiatric teams follow up abnormal results from physical health monitoring of patients in a secondary care clozapine clinic compared with follow-up in a specialist secondary care physical health clinic, using an audit/re-audit method of comparison. Prevalence data for cardiovascular risk factors within the clinic population were also obtained.

Results

Substantial and statistically significant (P < 0.01) improvements in follow-up of abnormal results were made following the introduction of a specialist clinic compared with treatment as usual. Prevalence of all cardiovascular risk factors among the patients on clozapine was very high compared with the general population.

Clinical implications

Patients on clozapine have significant and multiple cardiovascular risk factors, which may be best managed within a specialist secondary care physical health clinic that can follow up abnormal results and coordinate care across primary and secondary care.
‘Happiness-deficit disorder’? Prevention is better than cure
Authors: Kelly Brendan D.
Published: February 2011

Being happy is associated not only with better health, higher earnings and a longer life, but also with a stable family upbringing, stable financial situation, employment, good health, freedom and personal values. Psychiatrists may increase their patients' happiness by promoting effective, evidence-based mental healthcare. Individuals may enhance their own happiness by optimising physical and mental health; recognising the importance of personal values and happy communities; and optimising their financial situation. Government may boost citizens' happiness by deepening democracy; providing effective healthcare; supporting evidence-based well-being initiatives in communities; and then leaving citizens to seek out personal happiness in their own way.
Vandetanib Plus Pemetrexed for the Second-Line Treatment of Advanced Non–Small-Cell Lung Cancer: A Randomized, Double-Blind Phase III Trial
Authors: de Boer Richard H. , Arrieta Óscar , Yang Chih-Hsin , Gottfried Maya , Chan Valorie , Raats Johann , de Marinis Filippo , Abratt Raymond P. , Wolf Jürgen , Blackhall Fiona H. , Langmuir Peter , Milenkova Tsveta , Read Jessica , Vansteenkiste Johan F.
Published: February 2011

Purpose

Vandetanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling. This randomized, placebo-controlled phase III study assessed the efficacy of vandetanib plus pemetrexed as second-line therapy in advanced non–small-cell lung cancer.

Patients and Methods

Patients (N = 534) were randomly assigned to receive vandetanib 100 mg/d plus pemetrexed 500 mg/m2 every 21 days (n = 256) or placebo plus pemetrexed (n = 278). Progression-free survival (PFS) was the primary end point; overall survival, objective response rate, disease control rate, time to deterioration of symptoms, and safety were secondary assessments.

Results

There was no significant difference in PFS between treatment arms (hazard ratio [HR], 0.86; 97.58% CI, 0.69 to 1.06; P = .108). Overall survival was also not significantly different (HR, 0.86; 97.54% CI, 0.65 to 1.13; P = .219). Statistically significant improvements in objective response rate (19% v 8%; P < .001) and time to deterioration of symptoms (HR, 0.71; P = .0052; median, 18.1 weeks for vandetanib and 12.1 weeks for placebo) were observed in patients receiving vandetanib. Adding vandetanib to pemetrexed increased the incidence of some adverse events, including rash, diarrhea, and hypertension, while showing a reduced incidence of nausea, vomiting, anemia, fatigue, and asthenia with no reduction in the dose intensity of pemetrexed.

Conclusion

This study did not meet the primary end point of statistically significant PFS prolongation with vandetanib plus pemetrexed versus placebo plus pemetrexed. The vandetanib combination showed a significantly higher objective response rate and a significant delay in the time to worsening of lung cancer symptoms versus the placebo arm as well as an acceptable safety profile in this patient population.
Enhancing Patient-Provider Communication With the Electronic Self-Report Assessment for Cancer: A Randomized Trial
Authors: Berry Donna L. , Blumenstein Brent A. , Halpenny Barbara , Wolpin Seth , Fann Jesse R. , Austin-Seymour Mary , Bush Nigel , Karras Bryant T. , Lober William B. , McCorkle Ruth
Published: February 2011

Purpose

Although patient-reported cancer symptoms and quality-of-life issues (SQLIs) have been promoted as essential to a comprehensive assessment, efficient and efficacious methods have not been widely tested in clinical settings. The purpose of this trial was to determine the effect of the Electronic Self-Report Assessment–Cancer (ESRA-C) on the likelihood of SQLIs discussed between clinicians and patients with cancer in ambulatory clinic visits. Secondary objectives included comparison of visit duration between groups and usefulness of the ESRA-C as reported by clinicians.

Patients and Methods

This randomized controlled trial was conducted in 660 patients with various cancer diagnoses and stages at two institutions of a comprehensive cancer center. Patient-reported SQLIs were automatically displayed on a graphical summary and provided to the clinical team before an on-treatment visit (n = 327); in the control group, no summary was provided (n = 333). SQLIs were scored for level of severity or distress. One on-treatment clinic visit was audio recorded for each participant and then scored for discussion of each SQLI. We hypothesized that problematic SQLIs would be discussed more often when the intervention was delivered to the clinicians.

Results

The likelihood of SQLIs being discussed differed by randomized group and depended on whether an SQLI was first reported as problematic (P = .032). Clinic visits were similar with regard to duration between groups, and clinicians reported the summary as useful.

Conclusion

The ESRA-C is the first electronic self-report application to increase discussion of SQLIs in a US randomized clinical trial.
First-In-Man Study of CPX-351: A Liposomal Carrier Containing Cytarabine and Daunorubicin in a Fixed 5:1 Molar Ratio for the Treatment of Relapsed and Refractory Acute Myeloid Leukemia
Authors: Feldman Eric J. , Lancet Jeffrey E. , Kolitz Jonathan E. , Ritchie Ellen K. , Roboz Gail J. , List Alan F. , Allen Steven L. , Asatiani Ekatherine , Mayer Lawrence D. , Swenson Christine , Louie Arthur C.
Published: February 2011

Purpose

This phase I dose-escalation trial was performed to determine the maximum-tolerated dose, dose-limiting toxicities, and pharmacokinetics of CPX-351.

Patients and Methods

CPX-351 induction was administered on days 1, 3, and 5 by 90-minute infusion to 48 relapsed or refractory patients with acute myeloid leukemia (AML) or high-risk myelodysplasia. Doses started at 3 units/m2 with dose doublings in single-patient cohorts until a pharmacodynamic effect (treatment-related adverse events or reduction in bone marrow cellularity or blast count) was observed, followed by 33% escalations in three patient cohorts until dose-limiting toxicity (DLT) occurred.

Results

The maximum-tolerated dose was 101 units/m2. DLTs consisted of hypertensive crisis, congestive heart failure, and prolonged cytopenias. Adverse events were consistent with cytarabine and daunorubicin treatment. Response occurred at doses as low as 32 units/m2. Of 43 patients with AML, nine had complete response (CR) and one had CR with incomplete platelet recovery; of patients with acute lymphoblastic leukemia, one of three had CR. Eight CRs were achieved among the 31 patients with prior cytarabine and daunorubicin treatment. CR in AML occurred in five of 26 patients age ≥ 60 years and in five of 17 patients younger than age 60 years. Median half-life was 31.1 hours (cytarabine) and 21.9 hours (daunorubicin), with both drugs and their metabolites detectable > 7 days after the last dose. The targeted 5:1 molar ratio was maintained at all dose levels for up to 24 hours.

Conclusion

The recommended dose of CPX-351 for phase II study is 101 units/m2. Further exploration of efficacy and safety is ongoing in phase II trials in newly diagnosed and first-relapse patients with AML.
Phase I Study of Navitoclax (ABT-263), a Novel Bcl-2 Family Inhibitor, in Patients With Small-Cell Lung Cancer and Other Solid Tumors
Authors: Gandhi Leena , Camidge D. Ross , Ribeiro de Oliveira Moacyr , Bonomi Philip , Gandara David , Khaira Divis , Hann Christine L. , McKeegan Evelyn M. , Litvinovich Elizabeth , Hemken Philip M. , Dive Caroline , Enschede Sari H. , Nolan Cathy , Chiu Yi-Lin , Busman Todd , Xiong Hao , Krivoshik Andrew P. , Humerickhouse Rod , Shapiro Geoffrey I. , Rudin Charles M.
Published: February 2011

Purpose

Resistance to chemotherapy-induced apoptosis represents a major obstacle to cancer control. Overexpression of Bcl-2 is seen in multiple tumor types and targeting Bcl-2 may provide therapeutic benefit. A phase I study of navitoclax, a novel inhibitor of Bcl-2 family proteins, was conducted to evaluate safety, pharmacokinetics, and preliminary efficacy in patients with solid tumors.

Patients and Methods

Patients enrolled to intermittent dosing cohorts received navitoclax on day −3, followed by dosing on days 1 to 14 of a 21-day cycle. Patients on continuous dosing received a 1-week lead-in dose of 150 mg followed by continuous daily administration. Blood samples were collected for pharmacokinetic analyses, biomarker analyses, and platelet monitoring.

Results

Forty-seven patients, including 29 with small-cell lung cancer (SCLC) or pulmonary carcinoid, were enrolled between 2007 and 2008, 35 on intermittent and 12 on continuous dosing cohorts. Primary toxicities included diarrhea (40%), nausea (34%), vomiting (36%), and fatigue (34%); most were grade 1 or 2. Dose- and schedule-dependent thrombocytopenia was seen in all patients. One patient with SCLC had a confirmed partial response lasting longer than 2 years, and eight patients with SCLC or carcinoid had stable disease (one remained on study for 13 months). Pro-gastrin releasing peptide (pro-GRP) was identified as a surrogate marker of Bcl-2 amplification and changes correlated with changes in tumor volume.

Conclusion

Navitoclax is safe and well tolerated, with dose-dependent thrombocytopenia as the major adverse effect. Preliminary efficacy data are encouraging in SCLC. Efficacy in SCLC and the utility of pro-GRP as a marker of treatment response will be further evaluated in phase II studies.
Aspirin, Warfarin, or Enoxaparin Thromboprophylaxis in Patients With Multiple Myeloma Treated With Thalidomide: A Phase III, Open-Label, Randomized Trial
Authors: Palumbo Antonio , Cavo Michele , Bringhen Sara , Zamagni Elena , Romano Alessandra , Patriarca Francesca , Rossi Davide , Gentilini Fabiana , Crippa Claudia , Galli Monica , Nozzoli Chiara , Ria Roberto , Marasca Roberto , Montefusco Vittorio , Baldini Luca , Elice Francesca , Callea Vincenzo , Pulini Stefano , Carella Angelo M. , Zambello Renato , Benevolo Giulia , Magarotto Valeria , Tacchetti Paola , Pescosta Norbert , Cellini Claudia , Polloni Claudia , Evangelista Andrea , Caravita Tommaso , Morabito Fortunato , Offidani Massimo , Tosi Patrizia , Boccadoro Mario
Published: February 2011

Purpose

In patients with myeloma, thalidomide significantly improves outcomes but increases the risk of thromboembolic events. In this randomized, open-label, multicenter trial, we compared aspirin (ASA) or fixed low-dose warfarin (WAR) versus low molecular weight heparin (LMWH) for preventing thromboembolism in patients with myeloma treated with thalidomide-based regimens.

Patients and Methods

A total of 667 patients with previously untreated myeloma who received thalidomide-containing regimens and had no clinical indication or contraindication for a specific antiplatelet or anticoagulant therapy were randomly assigned to receive ASA (100 mg/d), WAR (1.25 mg/d), or LMWH (enoxaparin 40 mg/d). A composite primary end point included serious thromboembolic events, acute cardiovascular events, or sudden deaths during the first 6 months of treatment.

Results

Of 659 analyzed patients, 43 (6.5%) had serious thromboembolic events, acute cardiovascular events, or sudden death during the first 6 months (6.4% in the ASA group, 8.2% in the WAR group, and 5.0% in the LMWH group). Compared with LMWH, the absolute differences were +1.3% (95% CI, −3.0% to 5.7%; P = .544) in the ASA group and +3.2% (95% CI, −1.5% to 7.8%; P = .183) in the WAR group. The risk of thromboembolism was 1.38 times higher in patients treated with thalidomide without bortezomib. Three major (0.5%) and 10 minor (1.5%) bleeding episodes were recorded.

Conclusion

In patients with myeloma treated with thalidomide-based regimens, ASA and WAR showed similar efficacy in reducing serious thromboembolic events, acute cardiovascular events, and sudden deaths compared with LMWH, except in elderly patients where WAR showed less efficacy than LMWH.
Donor Lymphocyte Infusions Modulate Relapse Risk in Mixed Chimeras and Induce Durable Salvage in Relapsed Patients After T-Cell–Depleted Allogeneic Transplantation for Hodgkin's Lymphoma
Authors: Peggs Karl S. , Kayani Irfan , Edwards Noha , Kottaridis Panagiotis , Goldstone Anthony H. , Linch David C. , Hough Rachael , Morris Emma C. , Fielding Adele , Chakraverty Ronjon , Thomson Kirsty J. , Mackinnon Stephen
Published: February 2011

Purpose

Reduced-intensity conditioning has minimized nonrelapse-related mortality rates after allogeneic transplantation in patients with Hodgkin's lymphoma, and relapse has now become the major cause for treatment failure. We aimed to assess the impact of donor lymphocyte infusions (DLIs) on relapse incidence when administered for mixed chimerism and their utility as salvage therapy when given for relapse.

Patients and Methods

This study reports the outcomes of 76 consecutive patients with multiply relapsed or refractory Hodgkin's lymphoma who underwent allogeneic transplantation that incorporated in vivo T-cell depletion. Forty-two patients had related donors and 34 had unrelated donors. DLIs were administered in a dose-escalating fashion to 22 patients for mixed chimerism (median time of first dose, 9 months post-transplantation) and to 24 patients for relapse.

Results

Three-year donor lymphocyte–related mortality was 7%, relating mainly to the induction of graft-versus-host disease. Nineteen (86%) of 22 patients receiving donor lymphocytes for mixed chimerism converted to full donor status. Four-year relapse incidence was 5% in these 22 patients compared with 43% in patients who remained relapse free but full donor chimeras at 9 months post-transplantation (P = .0071). Nineteen (79%) of 24 patients receiving donor lymphocytes for relapse responded (14 complete responses, five partial responses). Four-year overall survival from relapse was 59% in recipients of donor lymphocytes, contributing to a 4-year overall survival from transplantation of 64% and a 4-year current progression-free survival of 59% in all 76 patients.

Conclusion

These data demonstrate the potential for allogeneic immunotherapy with donor lymphocytes both to reduce relapse risk and to induce durable antitumor responses in patients with Hodgkin's lymphoma after hematopoietic stem-cell transplantation that incorporates in vivo T-cell depletion.
Mammary-specific inactivation of E-cadherin and p53 impairs functional gland development and leads to pleomorphic invasive lobular carcinoma in mice
Authors: Derksen Patrick W. B. , Braumuller Tanya M. , van der Burg Eline , Hornsveld Marten , Mesman Elly , Wesseling Jelle , Krimpenfort Paul , Jonkers Jos
Published: February 2011

Breast cancer is the most common malignancy in women of the Western world. Even though a large percentage of breast cancer patients show pathological complete remission after standard treatment regimes, approximately 30–40% are non-responsive and ultimately develop metastatic disease. To generate a good preclinical model of invasive breast cancer, we have taken a tissue-specific approach to somatically inactivate p53 and E-cadherin, the cardinal cell-cell adhesion receptor that is strongly associated with tumor invasiveness. In breast cancer, E-cadherin is found mutated or otherwise functionally silenced in invasive lobular carcinoma (ILC), which accounts for 10–15% of all breast cancers. We show that mammary-specific stochastic inactivation of conditional E-cadherin and p53 results in impaired mammary gland function during pregnancy through the induction of anoikis resistance of mammary epithelium, resulting in loss of epithelial organization and a dysfunctional mammary gland. Moreover, combined inactivation of E-cadherin and p53 induced lactation-independent development of invasive and metastatic mammary carcinomas, which showed strong resemblance to human pleomorphic ILC. Dissemination patterns of mouse ILC mimic the human malignancy, showing metastasis to the gastrointestinal tract, peritoneum, lung, lymph nodes and bone. Our results confirm that loss of E-cadherin contributes to both mammary tumor initiation and metastasis, and establish a preclinical mouse model of human ILC that can be used for the development of novel intervention strategies to treat invasive breast cancer.
Structure and Energetics of Poly(Ethylene Glycol) Cationized by Li+, Na+, K+ and Cs+: A First-Principles Study
Authors: Memboeuf Antony , Vékey Károly , Lendvay György
Published: February 2011

Density functional theoretical methods, including several basis sets and two functionals, were used to collect information on the structure and energetic parameters of poly(ethylene glycol) (PEG), also referred to as poly(ethylene oxide) (PEO), coordinated by alkali metal ions. The oligomer chain is found to form a spiral around the alkali cation, which grows to roughly two helical turns when the oligomer size increases to about the decamer for each alkali ion. Above this size, the additional monomer units do not build the spiral further for Li+ and Na+; instead, they form less organized segments outside or next to the initial spiral. The distance of the first layer of coordinating O atoms from the alkali cation is 1.9–2.15 Å for Li+, 2.3–2.5 Å for Na+, 2.75–3.2 Å for K+ and 3.5–3.8 Å for Cs+ complexes. The number of O atoms in the innermost shell is five, six, seven and eleven for Li+, Na+, K+ and Cs+. The collision cross sections with He increase linearly with the oligomer to a very good approximation. No sign of leaning towards the 2/3 power dependence characterizing spherical particles is observed. The binding energy of the cation to the oligomer increases up to polymerization degree of about 10, where it levels off for each alkali-metal ion, indicating that this is approximately the limit of the oligomer size that can be influenced by the alkali cation. The binding energy–degree of polymerization curves are remarkably parallel for the four cations. The limiting binding energy at large polymerization degrees is about 544 kJ mol−1, 460 kJ mol−1, 356 kJ mol−1 and 314 kJ mol−1 for Li, Na, K and Cs, respectively. The geometrical features are compared with the X-ray and neutron diffraction data on crystalline and amorphous phases of conducting polymers formed by alkali-metal salts and PEG. The implications of the observations concerning collision cross sections and binding energies to ion mobility spectroscopy and mass spectrometry are discussed.
Gas Chromatography—Electron Ionization—Mass Spectrometry Analysis of O,O′-Dialkyl Methylphosphonites for Verification Analysis of the Chemical Weapons Convention
Authors: Pardasani Deepak , Tak Vijay , Purohit Ajay K. , Kanaujia Pankaj K. , Dubey Devendra K.
Published: February 2011

Gas chromatography–mass spectrometry (GC-MS) analysis of O,O′-dialkyl methylphosphonites (DAMPs) was carried out with a view to developing a database and understanding the mechanism of fragmentation. DAMPs are included in the list of schedule 2B4 chemicals of the Chemical Weapons Convention. GC-MS analysis of DAMPs and their deuterated analogs revealed that their fragmentations were dominated by α-cleavages, alkenyl radical loss and hydrogen rearrangements. Based on fragment ions of deuterated analogs and density functional theory calculations, the fragmentation routes were rationalized.