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The Radiation Therapy Committee of SWOG periodically evaluates its strategic plan in an effort to maintain a current and relevant scientific focus, and to provide a standard platform for future development of protocol concepts. Participants in the 2017 Strategic Planning Workshop included leaders in cancer basic sciences, molecular theragnostics, pharmaceutical and technology industries, clinical trial design, oncology practice, and statistical analysis. The committee discussed high-priority research areas, such as optimization of combined modality therapy, radiation oncology-specific drug design, identification of molecular profiles predictive of radiation-induced local or distant tumor responses, and methods for normal tissue-specific mitigation of radiation toxicity. The following concepts emerged as dominant questions ready for national testing: (i) what is the role of radiotherapy in the treatment of oligometastatic, oligorecurrent, and oligoprogressive disease? (ii) How can combined modality therapy be used to enhance systemic and local response? (iii) Can we validate and optimize liquid biopsy and other biomarkers (such as novel imaging) to supplement current response criteria to guide therapy and clinical trial design endpoints? (iv) How can we overcome deficiencies of randomized survival endpoint trials in an era of increasing molecular stratification factors? And (v) how can we mitigate treatment-related side effects and maximize quality of life in cancer survivors? The committee concluded that many aspects of these questions are ready for clinical evaluation and example protocol concepts are provided that could improve rates of cancer cure and quality of survival. Clin Cancer Res; 24(15); 3500-9. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Background and Objective: Respiratory syncytial virus (RSV) is the most significant cause of acute respiratory infection (ARI) in early life. RSV and other respiratory viruses are known to stimulate substantial outgrowth of potentially pathogenic bacteria in the upper airways of young children. However, the clinical significance of interactions between viruses and bacteria is currently unclear. The present study aimed to clarify the effect of viral and bacterial co-detections on disease severity during paediatric ARI., Methods: Nasopharyngeal aspirates from children under 2 years of age presenting with ARI to the emergency department were screened by quantitative PCR for 17 respiratory viruses and the bacterial pathogens Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis. Associations between pathogen detection and clinical measures of disease severity were investigated., Results: RSV was the most common virus detected, present in 29 of 58 samples from children with ARI (50%). Detection of S. pneumoniae was significantly more frequent during RSV infections compared to other respiratory viruses (adjusted effect size: 1.8, P: 0.03), and co-detection of both pathogens was associated with higher clinical disease severity scores (adjusted effect size: 1.2, P: 0.03)., Conclusion: Co-detection of RSV and S. pneumoniae in the nasopharynx was associated with more severe ARI, suggesting that S. pneumoniae colonization plays a pathogenic role in young children., (© 2017 Asian Pacific Society of Respirology.)

Myelodysplastic syndromes and chronic myelomonocytic leukemia are blood disorders characterized by ineffective hematopoiesis and progressive marrow failure that can transform into acute leukemia. The DNA methyltransferase inhibitor 5-azacytidine (AZA) is the most effective pharmacological option, but only ∼50% of patients respond. A response only manifests after many months of treatment and is transient. The reasons underlying AZA resistance are unknown, and few alternatives exist for non-responders. Here, we show that AZA responders have more hematopoietic progenitor cells (HPCs) in the cell cycle. Non-responder HPC quiescence is mediated by integrin α5 (ITGA5) signaling and their hematopoietic potential improved by combining AZA with an ITGA5 inhibitor. AZA response is associated with the induction of an inflammatory response in HPCs in vivo. By molecular bar coding and tracking individual clones, we found that, although AZA alters the sub-clonal contribution to different lineages, founder clones are not eliminated and continue to drive hematopoiesis even in complete responders., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)

Longitudinal studies are often used to investigate age-related developmental change. Whereas a single cohort design takes a group of individuals at the same initial age and follows them over time, an accelerated longitudinal design takes multiple single cohorts, each one starting at a different age. The main advantage of an accelerated longitudinal design is its ability to span the age range of interest in a shorter period of time than would be possible with a single cohort longitudinal design. This paper considers design issues for accelerated longitudinal studies. A linear mixed effect model is considered to describe the responses over age with random effects for intercept and slope parameters. Random and fixed cohort effects are used to cope with the potential bias accelerated longitudinal designs have due to multiple cohorts. The impact of other factors such as costs and the impact of dropouts on the power of testing or the precision of estimating parameters are examined. As duration-related costs increase relative to recruitment costs the best designs shift towards shorter duration and eventually cross-sectional design being best. For designs with the same duration but differing interval between measurements, we found there was a cutoff point for measurement costs relative to recruitment costs relating to frequency of measurements. Under our model of 30% dropout there was a maximum power loss of 7%.

Asthmatics are highly susceptible to respiratory viral infections, possibly due to impaired innate immunity. However, the exact mechanisms of susceptibility are likely to differ amongst viruses. Therefore, we infected primary nasal epithelial cells (NECs) from adults with mild-to-moderate asthma, with respiratory syncytial virus (RSV) or human metapneumovirus (hMPV) in vitro and investigated the antiviral response. NECs from these asthmatics supported elevated hMPV but not RSV infection, compared to non-asthmatic controls. This correlated with reduced apoptosis and reduced activation of caspase-9 and caspase-3/7 in response to hMPV, but not RSV. The expression of heat shock protein 70 (HSP70), a known inhibitor of caspase activation and subsequent apoptosis, was amplified in response to hMPV infection. Chemical inhibition of HSP70 function restored caspase activation and reduced hMPV infection in NECs from asthmatic subjects. There was no impairment in the production of IFN by NECs from asthmatics in response to either hMPV or RSV, demonstrating that increased infection of asthmatic airway cells by hMPV is IFN-independent. This study demonstrates, for the first time, a mechanism for elevated hMPV infection in airway epithelial cells from adult asthmatics and identifies HSP70 as a potential target for antiviral and asthma therapies., (© 2016 S. Karger AG, Basel.)

Background: The dyspnea accompanying advanced cardiorespiratory disease is often refractory to palliation. It is disabling, distressing and associated with the diseases most common everywhere in the world. The hand-held fan, used to generate a draught across the face, is a simple, cost-effective, safe, and universally applicable palliative breathlessness intervention, consistently described as valuable in qualitative research. A previous crossover trial confirmed its benefit in patients breathless at rest, but the washout period was uncertain., Aim: To determine the washout period after use of the hand-held fan to inform accurate randomized controlled trial design., Design: An observational methodological study. Breathlessness intensity was measured using 100 mm visual analog scale and numerical rating scale, and "relief of breathlessness" was measured on a 5-point scale. Those benefitting from the fan provided visual analog scale/numerical rating scale scores until (1) scores returned to baseline values or (2) until response had plateaued. The primary outcome measure was the time (in minutes) to reach either component of the primary study endpoint., Settings/participants: Four in-/out-patient hospice/hospital units; participants had chronic refractory breathlessness using the fan., Results: Overall, 31 patients participated (mean age: 74.8 years; range: 49-98 years, standard deviation = 11.5 years); 64% were males. Approximately, half of the sample experienced benefit of moderate effect size. The relative reduction in breathlessness relative to the mean baseline score for the sample was 27% for the visual analog scale and 19% for the numerical rating scale., Conclusion: Feasibility work is essential, even for simple widely employed interventions., (© The Author(s) 2015.)

Background: Recent studies have reported that asthma prevalence increases on migration to Australia. We hypothesised that changes in dietary intake contribute to this phenomenon. The aim of this study was to assess dietary intake in relation to migration status, length of stay in Australia and the association with self-reported wheeze., Methods: Students (n = 144) in a multicultural high school in Western Sydney completed the asthma symptoms ISAAC video questionnaire (AVQ3.0), spirometry and allergy skin prick tests. A dietitian administered a'Food Frequency' and 'Food Habits' questionnaire and a dietary history interview., Results: Students who spoke a language other than English, consumed a traditional or mixed dietary pattern, with lower consumption of saturated fat, compared to students who spoke English only. Saturated fat intake increased and fibre intake decreased with length of time in Australia. Intake of foods high in saturated or trans fatty acids were positively associated with length of stay in Australia. No associations between nutrient intake or whole food intake and self-reported wheeze were observed., Conclusion: As time progressed, dietary intake of immigrant children changed. While this was not associated with the development of wheeze in the students in this cohort, these changes are likely to have negative health consequences.

Background: Some people with progressive neurological diseases find they need additional support with eating and drinking at mealtimes, and may require artificial nutrition and hydration. Decisions concerning artificial nutrition and hydration at the end of life are ethically complex, particularly if the individual lacks decision-making capacity. Decisions may concern issues of life and death: weighing the potential for increasing morbidity and prolonging suffering, with potentially shortening life. When individuals lack decision-making capacity, the standard processes of obtaining informed consent for medical interventions are disrupted. Increasingly multi-professional groups are being utilised to make difficult ethical decisions within healthcare. This paper reports upon a service evaluation which examined decision-making within a UK hospital Feeding Issues Multi-Professional Team., Methods: A three month observation of a hospital-based multi-professional team concerning feeding issues, and a one year examination of their records. The key research questions are: a) How are decisions made concerning artificial nutrition for individuals at risk of lacking decision-making capacity? b) What are the key decision-making factors that are balanced? c) Who is involved in the decision-making process?, Results: Decision-making was not a singular decision, but rather involved many different steps. Discussions involving relatives and other clinicians, often took place outside of meetings. Topics of discussion varied but the outcome relied upon balancing the information along four interdependent axes: (1) Risks, burdens and benefits; (2) Treatment goals; (3) Normative ethical values; (4) Interested parties., Conclusions: Decision-making was a dynamic ongoing process with many people involved. The multiple points of decision-making, and the number of people involved with the decision-making process, mean the question of 'who decides' cannot be fully answered. There is a potential for anonymity of multiple decision-makers to arise. Decisions in real world clinical practice may not fit precisely into a model of decision-making. The findings from this service evaluation illustrate that within multi-professional team decision-making; decisions may contain elements of both substituted and supported decision-making, and may be better represented as existing upon a continuum.

Non-small cell lung cancer (NSCLC) is a leading cause of death worldwide. Targeted monotherapies produce high regression rates, albeit for limited patient subgroups, who inevitably succumb. We present a novel strategy for identifying customized combinations of triplets of targeted agents, utilizing a simplified interventional mapping system (SIMS) that merges knowledge about existent drugs and their impact on the hallmarks of cancer. Based on interrogation of matched lung tumor and normal tissue using targeted genomic sequencing, copy number variation, transcriptomics, and miRNA expression, the activation status of 24 interventional nodes was elucidated. An algorithm was developed to create a scoring system that enables ranking of the activated interventional nodes for each patient. Based on the trends of co-activation at interventional points, combinations of drug triplets were defined in order to overcome resistance. This methodology will inform a prospective trial to be conducted by the WIN consortium, aiming to significantly impact survival in metastatic NSCLC and other malignancies.

The aim if this study was to investigate the hypothesis that K-RAS 4A is upregulated in a mineralocorticoid-dependent manner in renal cell carcinoma and that this supports the proliferation and survival of some renal cancers. Expression of the K-RAS in renal tumour tissues and cell lines was examined by real-time PCR and Western blot and mineralocorticoid receptor, and its gatekeeper enzyme 11β-hydroxysteroid dehydrogenase-2 was examined by immunocytochemistry on a tissue microarray of 27 cases of renal cell carcinoma. Renal cancer cells lines 04A018 (RCC4 plus VHL) and 04A019 (RCC4 plus vector alone) were examined for the expression of K-RAS4A and for the effect on K-RAS expression of spironolactone blockade of the mineralocorticoid receptor. K-RAS4A was suppressed by siRNA, and the effect on cell survival, proliferation and activation of the Akt and Raf signalling pathways was investigated in vitro. K-RAS4A was expressed in RCC tissue and in the renal cancer cell lines but K-RAS was downregulated by spironolactone and upregulated by aldosterone. Spironolactone treatment and K-RAS suppression both led to a reduction in cell number in vitro. Both Akt and Raf pathways showed activation which was dependent on K-RAS expression. K-RAS expression in renal cell carcinoma is at least partially induced by aldosterone. Aldosterone supports the survival and proliferation of RCC cells by upregulation of K-RAS acting through the Akt and Raf pathways., (© 2014 The Authors. International Journal of Experimental Pathology © 2014 International Journal of Experimental Pathology.)

Recent approvals for oncology drugs have seen an increasing proportion directed to specific genetic targets identified with an associated companion diagnostic test. In addition, there is a wave of drugs directed against immune 'checkpoints' which promise to transform the way cancer is treated in the next decade. We can increase the probability of success in drug development based on a thorough mechanistic understanding of how a target drug affects cancer biology and the specific biological and genotypic context in which it operates. This article compares and contrasts the discovery and development of gefitinib-the first EGFR tyrosine kinase inhibitor and AZD9291, an irreversible inhibitor of both sensitizing and resistant mutated EGFR. This demonstrates how the better understanding we now have of the genetic changes driving the cancer growth and the biochemical structure and function of the mutated proteins, has led to a much faster developmental path with higher likelihood of success in pivotal trials. An emerging trend in response to the challenge of the increasing segmentation of cancers based on their genetic makeup is the development of 'basket' studies which include one or more screening tests for multiple genetic aberrations and the direction of patients to one of several arms of a clinical trial based on the specific aberration in their tumor. In the face of both the wealth of genetic information about cancer and the challenges of drug development, collaboration across academia and industry is vital. There is great potential to benefit from more 'open innovation' to address some of these challenges and opportunities. Far from there being a decline in innovation in pharmaceutical development, I see that we are in one of the most exciting times in cancer drug development with innovation in every aspect of how we discover and develop new therapies.

Decisions about percutaneous endoscopic gastrostomy (PEG) can be clinically and ethically challenging, particularly when patients lack decision-making capacity. As the age of the UK population rises, with the associated increase in prevalence of dementias and neurodegenerative diseases, it is becoming an increasingly important issue for clinicians. The recent review and subsequent withdrawal of the Liverpool Care Pathway highlighted feeding as a particular area of concern. The authors undertook a 1-year retrospective review of individuals referred to the feeding issues multidisciplinary team (FIMDT) at Addenbrooke's Hospital, Cambridge, UK, in 2011. The majority of patients referred (n = 158) had a primary diagnosis of cancer (44%). The second largest group was those who had had a stroke or brain haemorrhage (13%). Twenty-eight per cent of patients had no, or uncertain, decision-making capacity on at least one occasion during decision-making. There are reflections on the role of a multidisciplinary team in the process of decision-making for these complex patients., (© 2014 Royal College of Physicians.)

In response to increasing evidence that advertising of foods and beverages affects children's food choices and food intake, several national governments and many of the world's larger food and beverage manufacturers have acted to restrict the marketing of their products to children or to advertise only 'better for you' products or 'healthier dietary choices' to children. Independent assessment of the impact of these pledges has been difficult due to the different criteria being used in regulatory and self-regulatory regimes. In this paper, we undertook a systematic review to examine the data available on levels of exposure of children to the advertising of less healthy foods since the introduction of the statutory and voluntary codes. The results indicate a sharp division in the evidence, with scientific, peer-reviewed papers showing that high levels of such advertising of less healthy foods continue to be found in several different countries worldwide. In contrast, the evidence provided in industry-sponsored reports indicates a remarkably high adherence to voluntary codes. We conclude that adherence to voluntary codes may not sufficiently reduce the advertising of foods which undermine healthy diets, or reduce children's exposure to this advertising., (© 2013 The Authors. obesity reviews © 2013 International Association for the Study of Obesity.)

Some hepatitis C (HCV)-uninfected, high-risk individuals have HCV-specific cellular immunity without viraemia or seroconversion. The characteristics of these responses and the risk behavioural associations were studied in 94 subjects in a prospective cohort of recently seronegative prisoners reporting injecting drug use (IDU). Detailed behavioural data were collected. HCV antibody and PCR testing were performed. ELISpot assays for HCV-induced interferon (IFN)-γ and interleukin (IL)-2 production by T lymphocytes, as well as multiplex in vitro cytokine production assays, were performed. Seventy-eight subjects remained antibody and PCR negative and 16 seroconverted. Of the seronegative group, 22 (28%) had IFN-γ ELISpot responses in comparison with 13 of the 16 seroconverters (82%). This seronegative immune status was associated positively with injecting anabolic steroids and negatively with a recent break from IDU. The IFN-γ ELISpot responses involved both CD4 and CD8 T lymphocytes and were comparable in magnitude, but narrower in specificity, in uninfected subjects than in seroconverters. A subset of seronegative subjects had HCV-induced cytokine production patterns comparable with the seroconverters with increased production of IFN-γ, IL-2 and tumour necrosis factor (TNF)-α and reduced IL-10 in response to nonstructural peptides. In conclusion, comparable patterns of HCV-specific cellular immunity are found in recently infected subjects and in a minority of high-risk, uninfected subjects. Further characterization of these responses and their protective efficacy will inform HCV vaccine development., (© 2012 Blackwell Publishing Ltd.)

Purpose: We looked for herpes simplex virus types 1 and 2 (HSV-1 and HSV-2, respectively), varicella zoster virus (VZV), Epstein-Barr virus (EBV) and cytomegalovirus (CMV) DNA in Malawian adults with clinically suspected meningitis., Methods: We collected cerebrospinal fluid (CSF) from consecutive adults admitted with clinically suspected meningitis to Queen Elizabeth Central Hospital (QECH), Blantyre, Malawi, for a period of 3 months. Those with proven bacterial or fungal meningitis were excluded. Real-time polymerase chain reaction (PCR) was performed on the CSF for HSV-1 and HSV-2, VZV, EBV and CMV DNA., Results: A total of 183 patients presented with clinically suspected meningitis. Of these, 59 (32 %) had proven meningitis (bacterial, tuberculous or cryptococcal), 39 (21 %) had normal CSF and 14 (8 %) had aseptic meningitis. For the latter group, a herpes virus was detected in 9 (64 %): 7 (50 %) had EBV and 2 (14 %) had CMV, all were human immunodeficiency virus (HIV)-positive. HSV-2 and VZV were not detected. Amongst those with a normal CSF, 8 (21 %) had a detectable herpes virus, of which 7 (88 %) were HIV-positive., Conclusions: The spectrum of causes of herpes viral meningitis in this African population is different to that in Western industrialised settings, with EBV being frequently detected in the CSF. The significance of this needs further investigation.

Ipilimumab, a fully human monoclonal antibody, which blocks cytotoxic T-lymphocyte antigen-4, has demonstrated an improvement in overall survival in 2 phase III trials of patients with advanced melanoma. To gain an understanding of its mechanism of action, the effects of ipilimumab on T-cell populations and on humoral immune responses were studied in patients with advanced melanoma from 2 phase II trials. Antibody levels against 5 tumor antigens were assessed at baseline and up to 12 weeks after ipilimumab treatment. Serologic reactivity to the cancer-testis antigen NY-ESO-1 increased by at least 5-fold at week 12 of treatment in 10% to 13% of patients. Increased antibody levels were also observed to the tumor antigens Melan-A, MAGE-A4, SSX2, and p53. Immunocompetence was evaluated with tetanus boosters administered before ipilimumab and pneumococcal and influenza vaccines given 5 days after ipilimumab treatment. At week 7, most patients who received ipilimumab and vaccine showed greater humoral responses relative to baseline titers. For peripheral T-cell populations, statistically significant increases in the percent of activated (HLA-DR) CD4 and CD8 T cells with concomitant decreases in naive CD4 and CD8 T cells were observed after ipilimumab treatment. These changes were evident by week 4 of treatment. Increases were also observed in central memory, effector memory, and activated ICOS CD4 T cells, but not in ICOS CD8 T cells or in FoxP3 CD4 regulatory T cells. These results suggest that ipilimumab can enhance immune responses mediated by different T-cell populations, and humoral immunity, in melanoma patients.

Mortality from adult bacterial meningitis exceeds 50% in sub-Saharan Africa. We postulated that-particularly in individuals infected with human immunodeficiency virus (HIV)-herpes simplex virus, varicella zoster virus, Epstein-Barr virus (EBV), and cytomegalovirus (CMV) in the cerebrospinal fluid (CSF) contribute to poor outcome. CSF from 149 Malawian adults with bacterial meningitis and 39 controls were analyzed using polymerase chain reaction. EBV was detected in 79 of 149 bacterial meningitis patients. Mortality (54%) was associated with higher CSF EBV load when adjusted for HIV (P = .01). CMV was detected in 11 of 115 HIV-infected patients, 8 of whom died. The mechanisms by which EBV and CMV contribute to poor outcome require further investigation.

Model selection procedures for simultaneous analysis of all single-nucleotide polymorphisms in genome-wide association studies are most suitable for making full use of the data for a complex disease study. In this paper we consider a penalized regression using the LASSO procedure and show that post-processing of the penalized-regression results with subsequent stepwise selection may lead to improved identification of causal single-nucleotide polymorphisms.

Background: Several infections trigger postinfective fatigue syndromes, which share key illness characteristics with each other and with chronic fatigue syndrome (CFS). Previous cross-sectional case-control studies of CFS have suggested that unique gene expression signatures are evident in peripheral blood samples., Methods: Peripheral blood transcriptomes in samples collected longitudinally, in 18 subjects with a fatigue syndrome lasting ≥ 6 months after acute infection due to Epstein-Barr virus, Ross River virus, or Coxiella burnetii (Q fever), and 18 matched control subjects who had recovered promptly, were studied by microarray (n = 127) and confirmatory quantitative polymerase chain reaction (PCR). Gene expression patterns associated with CFS were sought by univariate statistics and regression modeling., Results: There were 23 genes with modest differential expression (0.6-2.3-fold change) in within-subject comparisons of early, symptomatic time points with late, recovered time points. There were modest differences found in 63 genes, either in cross-sectional comparison of cases and controls at 6 months after infection onset or in the regression model. There were 223 genes significantly correlated with individual symptom domains. Quantitative PCR confirmed 33 (73%) of 45 genes-none were consistent across cohorts., Conclusions: Although the illness characteristics of patients with postinfective fatigue syndromes have more similarities than differences, no reliable peripheral blood gene expression correlate is evident.

Background: The objectives of this phase I study were to determine the safety, pharmacokinetics (PK), pharmacodynamics and efficacy of brivanib combined with full-dose cetuximab in patients with advanced gastrointestinal malignancies., Methods: Patients with advanced gastrointestinal malignancies who had failed prior therapies received brivanib (320, 600 or 800 mg daily) plus cetuximab (400 mg m(-2) loading dose then 250 mg m(-2) weekly). Assessments included adverse events, PK, tumour response, 2[18F]fluoro-2-deoxyglucose positron-emitting tomography and K-Ras mutation analyses., Results: Toxicities observed were manageable; the most common treatment-related toxicities (>10% of patients) were fatigue, diarrhoea, anorexia, increase in aspartate aminotransferase and alanine aminotransferase, acneiform dermatitis, headache, mucosal inflammation, nausea, dry skin, vomiting, hypertension, pruritus, proteinuria and weight loss. Of 62 patients, 6 (9.7%) had objective radiographic partial responses, with an overall response rate of 10%. Median duration of response was 9.2 months; median progression-free survival was 3.9 months., Conclusions: The acceptable toxicity profile and efficacy of brivanib observed in this study were promising. These findings are being further evaluated in a phase III study of brivanib plus cetuximab vs cetuximab alone in patients previously treated with combination chemotherapy for K-Ras wild-type advanced metastatic colorectal cancer.

The synthesis and biological evaluation of non-oxime pyrazole based B-Raf inhibitors is reported. Several oxime replacements have been prepared and have shown excellent enzyme activity. Further optimization of fused pyrazole 2a led to compound 38, a selective and potent B-Raf inhibitor., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Background: This study was designed to determine the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of brivanib in patients with advanced/metastatic solid tumors., Patients and Methods: Ninety patients enrolled in this two-part, phase I open-label study of oral brivanib alaninate. The primary objectives of this study were (in part A) dose-limiting toxicity, maximum tolerated dose (MTD) and the lowest biologically active dose level and (in part B) the optimal dose/dose range. The secondary objectives of this study were preliminary evidence of antitumor activity, PK and PD., Results: Across part A (open-label dose escalation and MTD) and part B (open-label dose optimization), 68 patients received brivanib alaninate. Brivanib demonstrated a manageable toxicity profile at doses of 180-800 mg. Most toxic effects were mild. Systemic exposure of the active moiety brivanib increased linearly ≤1000 mg/day. The MTD was 800 mg/day. Forty-four patients were treated at the MTD: 20 with 800 mg continuously, 11 with 800 mg intermittently and 13 with 400 mg b.i.d. doses. Partial responses were confirmed in two patients receiving brivanib ≥600 mg. Dynamic contrast-enhanced magnetic resonance imaging demonstrated statistically significant decreases in parameters reflecting tumor vascularity and permeability after multiple doses in the 800-mg continuous q.d. and 400-mg b.i.d. dose cohorts., Conclusion: In patients with advanced/metastatic cancer, brivanib demonstrates promising antiangiogenic and antitumor activity and manageable toxicity at doses ≤800 mg orally q.d., the recommended phase II study dose.

Purpose of Review: Breathlessness is difficult to palliate and nonpharmacological interventions are effective management strategies currently available for mobile patients. These are a diverse group of interventions, currently poorly defined and inconsistently used. This review concentrates on identifying and recommending the most effective nonpharmacological strategies for breathlessness, to aid clinical practice., Recent Findings: Much of the evidence presented is based on a Cochrane Review, which demonstrated that facial cooling, by handheld fan, mobility aids (e.g. rollators) and neuromuscular electrical stimulation all had evidence to support their use in breathlessness. Breathing exercises, pacing and positioning are frequently used to manage breathlessness, but need definition and further research. Anxiety reduction techniques and carer support are used in chronic disease management and applicable for breathlessness, but act indirectly. Exercise is a long established management strategy in both respiratory and other chronic diseases to maintain fitness (which reduces breathlessness) and increase psychological well being., Summary: All patients with breathlessness should learn appropriate nonpharmacological interventions. Some can be taught by clinicians without specialist training, but others require specialist skills and high levels of engagement by cognitively intact and highly motivated people. Specialist breathlessness services may be more effective in delivering complex nonpharmacological interventions, but more research is needed.

Study Objectives: Disturbances of the internal biological clock manifest as fatigue, poor concentration, and sleep disturbances-symptoms reminiscent of chronic fatigue syndrome (CFS) and suggestive of a role for circadian rhythm disturbance in CFS. We examined circadian patterns of activity, sleep, and cortisol secretion in patients with CFS., Design: Case-control study, 5-day behavioral observation., Setting: Natural setting/home environment, Participants: 15 patients with CFS and 15 healthy subjects of similar age, sex, body mass index (BMI), and activity levels., Interventions: N/A., Measurements: Self-report questionnaires were used to obtain medical history and demographic information and to assess health behaviors, somatic and psychological symptoms, and sleep quality. An actiwatch accelerometer recorded activity and sleep patterns over 5 days with concurrent activity and symptom logs. Diurnal salivary cortisol secretion was measured. Additionally, overnight heart rate monitoring and pain sensitivity assessment was undertaken., Results: Ratings of symptoms, disability, sleep disturbance, and pain sensitivity were greater in patients with CFS. No between-group differences were found in the pattern or amount of sleep, activity, or cortisol secretion. Afternoon activity levels significantly increased evening fatigue in patients but not control subjects. Low nocturnal heart rate variability was identified as a biological correlate of unrefreshing sleep., Conclusions: We found no evidence of circadian rhythm disturbance in CFS. However, the role of autonomic activity in the experience of unrefreshing sleep warrants further assessment. The activity symptom-relationship modelled here is of clinical significance in the approach to activity and symptom management in the treatment of CFS.

c-Abl kinase activity is regulated by a unique mechanism involving the formation of an autoinhibited conformation in which the N-terminal myristoyl group binds intramolecularly to the myristoyl binding site on the kinase domain and induces the bending of the αI helix that creates a docking surface for the SH2 domain. Here, we report a small-molecule c-Abl activator, DPH, that displays potent enzymatic and cellular activity in stimulating c-Abl activation. Structural analyses indicate that DPH binds to the myristoyl binding site and prevents the formation of the bent conformation of the αI helix through steric hindrance, a mode of action distinct from the previously identified allosteric c-Abl inhibitor, GNF-2, that also binds to the myristoyl binding site. DPH represents the first cell-permeable, small-molecule tool compound for c-Abl activation., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The development of inhibitors of B-Raf(V600E) serine-threonine kinase is described. Various head-groups were examined to optimize inhibitor activity and ADME properties. Several of the head-groups explored, including naphthol, phenol and hydroxyamidine, possessed good activity but had poor pharmacokinetic exposure in mice. Exposure was improved by incorporating more metabolically stable groups such as indazole and tricyclic pyrazole, while indazole could also be optimized for good cellular activity., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Blockade of cytotoxic T-lymphocyte antigen-4 (CTLA-4) by ipilimumab leads to immune-mediated tumor regression and immune-related adverse events (irAEs), including diarrhea and colitis. The current analyses were undertaken to promote an understanding of the underlying mechanism of action and to identify potential biomarkers that could help in the prediction and management of ipilimumab-induced gastrointestinal irAEs. Treatment-naïve or previously treated patients with unresectable stage III/IV melanoma (n = 115) received open-label ipilimumab (10 mg/kg every 3 weeks for four doses) and were randomized to receive concomitant blinded prophylactic oral budesonide (9 mg/d with gradual taper through week 16) or placebo. Outcome measures included histologic assessment of bowel biopsies and assessment of serologic markers of inflammatory bowel disease (IBD), fecal calprotectin levels, and polymorphisms in immune-related genes. Ipilimumab resulted in dysregulation of gastrointestinal mucosal immunity as evidenced by altered antibody levels to enteric flora, inflammatory cell infiltration into gastrointestinal mucosa, and increased fecal calprotectin associated with diarrhea and clinical evidence of colitis. The pattern of ipilimumab-induced antibody titers to microbial flora and the histologic features and location of the inflammation were distinct from classic IBD. Prophylactic budesonide did not prevent ipilimumab-induced bowel inflammation. Despite an observed association between colonic inflammation and grade 2 or higher diarrhea, no baseline biomarkers could reliably predict development of gastrointestinal toxicity. Although classic IBD and ipilimumab-related gastrointestinal toxicity are both immune mediated, the observed pattern of biomarkers suggests ipilimumab-related gastrointestinal toxicity may be a distinct clinicopathologic entity.

Statistical analysis is critical in the interpretation of experimental data across the life sciences, including neuroscience. The nature of the data collected has a critical role in determining the best statistical approach to take. One particularly prevalent type of data is referred to as "clustered data." Clustered data are characterized as data that can be classified into a number of distinct groups or "clusters" within a particular study. Clustered data arise most commonly in neuroscience when data are compiled across multiple experiments, for example in electrophysiological or optical recordings taken from synaptic terminals, with each experiment providing a distinct cluster of data. However, there are many other types of experimental design that can yield clustered data. Here, we provide a statistical model for intracluster correlation and systematically investigate a range of methods for analyzing clustered data. Our analysis reveals that it is critical to take data clustering into account and suggests appropriate statistical approaches that can be used to account for data clustering.

Multiple strategies have been used in an effort to increase the pool of organs for transplantation. Standardizing donor management has produced promising results. Donor management goals (DMGs) are now being used as end points of intensive care unit care during the prerecovery phase but no prospective results have been reported. Data from the United Network for Organ Sharing Region 11 were collected for successful achievement of eight common donor management goals (mean airway pressure [MAP], central venous pressure [CVP], pH, PaO2, sodium, glucose, single pressor use, and urine output) before organ recovery. Two time periods were studied with different panels of DMGs. The analysis identified the success rate of transplantation. Goals were stratified by their statistical correlation with the number of organs transplanted per donor (OTPD) in an effort to identify the most important parameter(s). Eight hundred five organ donors were studied with 2685 organs transplanted. DMGs were assessed through two phases of the study. Achieving DMGs rose from 18 to 66 per cent associated with significant improvement in OTPD (range, 2.96 to 3.45). The success of transplantation was primarily associated with limitations in vasopressor use and PaO2. Tight glucose control did affect the rate of pancreatic transplants. Thoracic organs were the most sensitive to DMGs with a 10- to 15-fold increase in lung transplantation when PaO2 rose above 100 mmHg. MAP, CVP, pH, sodium, and urine output had little effect on transplantation. Standardization of end points of donor management was associated with increased rates of transplantation. Surprisingly, not all standard goals are necessary for optimal organ use. The most significant parameters were the low use of vasopressor agents and oxygenation. Donor management strategies should strive to optimize these goals.

Context: Dyspnea is a disabling distressing symptom that is common in advanced disease affecting millions of people worldwide. Current palliative strategies are partially effective in managing this symptom; facial cooling has been shown to reduce the sensation of breathlessness when induced in volunteers but has not been formally investigated in dyspnea associated with disease., Objective: The objective of this study was to investigate whether a handheld fan reduces the sensation of breathlessness in such patients, enhancing palliative approaches., Methods: The effectiveness of a handheld fan (blowing air across the nose and mouth) in reducing the sensation of breathlessness was assessed in patients with advanced disease. Fifty participants were randomized to use a handheld fan for five minutes directed to their face or leg first and then crossed over to the other treatment. The primary outcome measure was a decrease of greater than 1cm in breathlessness recorded on a 10 cm visual analog scale (VAS)., Results: There was a significant difference in the VAS scores between the two treatments, with a reduction in breathlessness when the fan was directed to the face (P=0.003)., Conclusion: This study supports the hypothesis that a handheld fan directed to the face reduces the sensation of breathlessness. The fan was acceptable to participants: it is inexpensive, portable, enhances self-efficacy, and available internationally. It should be recommended as part of a palliative management strategy for reducing breathlessness associated with advanced disease., (Copyright 2010 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.)

Tumor angiogenesis is a complex and tightly regulated network mediated by various proangiogenic factors. The fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) family of growth factors, and associated tyrosine kinase receptors have a major influence in tumor growth and dissemination and may work synergistically to promote angiogenesis. Brivanib alaninate is the orally active prodrug of brivanib, a selective dual inhibitor of FGF and VEGF signaling. Here, we show that brivanib demonstrates antitumor activity in a broad range of xenograft models over multiple dose levels and that brivanib alaninate shows dose-dependent efficacy equivalent to brivanib in L2987 human tumor xenografts. Brivanib alaninate (107 mg/kg) reduced tumor cell proliferation as determined by a 76% reduction in Ki-67 staining and reduced tumor vascular density as determined by a 76% reduction in anti-CD34 endothelial cell staining. Furthermore, Matrigel plug assays in athymic mice showed that brivanib alaninate inhibited angiogenesis driven by VEGF or basic FGF alone, or combined. Dynamic contrast-enhanced magnetic resonance imaging, used to assess the effects of brivanib alaninate on tumor microcirculation, showed a marked decrease in gadopentetate dimeglumine contrast agent uptake at 107 mg/kg dose, with a reduction in area under the plasma concentration-time curve from time 0 to 60 minutes at 24 and 48 hours of 54% and 64%, respectively. These results show that brivanib alaninate is an effective antitumor agent in preclinical models across a range of doses, and that efficacy is accompanied by changes in cellular and vascular activities.

Aicardi-Goutières syndrome is a primarily autosomal recessive disorder characterized by congenital encephalopathy, basal ganglia calcifications, elevated interferon-alpha in blood and cerebral spinal fluid, and negative studies for intrauterine infections that can mimic the syndrome. Cutaneous manifestations include pernio, photosensitivity, and cutaneous vasculitis. We present a case of Aicardi-Goutières syndrome to increase awareness of the disorder and its possible relation to systemic lupus erythematosus.

Neonatal lupus erythematosus is an uncommon disease caused by transplacental passage of maternal anti-Ro (SS-A), anti-LA (SS-B), or anti-U1RNP antibodies. Cutaneous findings of neonatal lupus are variable, but annular, erythematous plaques occurring within a few weeks of birth are most typical. Cutaneous lesions of congenital onset lupus erythematosus can differ from that of neonatal lupus erythematosus, presenting with atrophy or scarring, and less commonly, erosions. We report an unusual case of congenital lupus erythematosus presenting at birth with widespread erosions, pancytopenia, and subsequent hepatobiliary disease.

Although drugs used to treat several neurological diseases are presumed to target synapses that secrete dopamine (DA), relatively little is known about synaptic vesicle (SV) release mechanisms at single DA synapses. We found that the relative probability of release (Pr) varied between individual DA synapses. Furthermore, DA terminals generally exhibited lower Pr than glutamatergic hippocampal (Hpc) terminals, suggesting that DA release is less reliable than the release of glutamate. Our mathematical model of fluorescence loss shows that Pr is regulated by two independent and heterogeneous elements. First, the size of the recycling SV pool regulates Pr. Second, Pr is also independently regulated by additional factors, which are reflected in the time constant of FM 1-43 destaining, tau. We found that the observed difference in Pr between Hpc and DA neurons results because the recycling SV pool is smaller in DA neurons than in Hpc neurons. However, tau does not vary between these two neuron populations. We also identified a population of functional nonsynaptic boutons in DA axons, which are not associated with a postsynaptic element and which are not functionally different from boutons that formed conventional synapses. Our work provides a new approach to the study of SV exocytosis in DA neurons and shows that synaptic terminals of DA neurons are functionally heterogeneous and differ from excitatory terminals in terms of Pr.

It has long been proposed that excitotoxicity contributes to nerve cell death in neurodegenerative diseases. Activin A, a member of the transforming growth factor-beta superfamily, is expressed by neurons following excitotoxicity. We show for the first time that this activin A expression is essential for neurogenesis to proceed following neurodegeneration. We found that intraventricular infusion of activin A increased the number of newborn neurons in the dentate gyrus, CA3, and CA1 layers of the normal adult hippocampus and also, following lipopolysaccharide administration, had a potent inhibitory effect on gliosis in vivo and on microglial proliferation in vivo and in vitro. Consistent with the role of activin A in regulating central nervous system inflammation and neurogenesis, intraventricular infusion of follistatin, an activin A antagonist, profoundly impaired neurogenesis and increased the number of microglia and reactive astrocytes following onset of kainic acid-induced neurodegeneration. These results show that inhibiting endogenous activin A is permissive for a potent underlying inflammatory response to neurodegeneration. We demonstrate that the anti-inflammatory actions of activin A account for its neurogenic effects following neurodegeneration because co-administration of nonsteroidal anti-inflammatory drugs reversed follistatin's inhibitory effects on neurogenesis in vivo. Our work indicates that activin A, perhaps working in conjunction with other transforming growth factor-beta superfamily molecules, is essential for neurogenesis in the adult central nervous system following excitotoxic neurodegeneration and suggests that neurons can regulate regeneration by suppressing the inflammatory response, a finding with implications for understanding and treating acute and chronic neurodegenerative diseases.

Purpose: This phase II study evaluated the efficacy and safety of ixabepilone as neoadjuvant therapy for invasive breast cancer not amenable to breast conservation surgery. Gene expression studies were undertaken using genes that were identified as potentially associated with sensitivity/resistance to ixabepilone in prior preclinical investigations., Patients and Methods: Patients with invasive breast cancer >or= 3 cm were eligible. Ixabepilone 40 mg/m(2) was administered as a 3-hour intravenous infusion on day 1 of a 21-day cycle for four or fewer cycles., Results: One hundred sixty-one patients were treated. The overall complete pathologic response (pCR) rate was 18% in breast and 29% in estrogen receptor (ER) -negative patients. Gene expression data were available for 134 patients. ER gene expression (ER1) was inversely related to pCR in breast and had a positive predictive value (PPV) of 37% and negative predictive value (NPV) of 92%. A 10-gene penalized logistic regression (PLR) model developed from 200 genes predictive of ixabepilone sensitivity in preclinical experiments included ER and tau and had higher PPV (45%) and comparable NPV (89%) to ER1. Grade 3 to 4 adverse events (AEs) were reported for 32% of patients. Except for neutropenia and leukopenia, all grade 3 to 4 AEs occurred in

Purpose: Dasatinib (BMS-354825) is a potent, oral multi-targeted kinase inhibitor. It is an effective therapy for patients with imatinib-resistant or -intolerant Ph+ leukemias,. It has demonstrated promising preclinical anti-tumor activity, and is under clinical evaluation in solid tumors. To support the clinical development of dasatinib, we identified a pharmacodynamic biomarker to assess in vivo SRC kinase inhibition, with subsequent evaluation in cancer patients., Methods: The biomarker, phosphorylated SRC (phospho-SRC), was first identified in human prostate PC-3 tumor cells and peripheral blood mononuclear cells (PBMCs) in vitro. It was further assessed in nude mice bearing PC-3 xenografts. Phospho-SRC[pY418] in tumors and PBMC were measured by western blot analysis, and were quantified by ELISA assays. Dasatinib plasma concentrations were determined using LC/MS/MS., Results: In PC-3 cells, dasatinib showed dose-dependent anti-proliferative effect, which correlated with the inhibition of phospho-SRC[pY418] and of SRC kinase activity. With a single oral dose of 50 or 15 mg/kg, tumoral phospho-SRC[pY418] was maximally inhibited at 3 h, partially reversed between 7 and 17 h, and completely recovered after 24 h post dose. At 5 mg/kg, tumoral phospho-SRC[pY418] inhibition was less pronounced and recovered more rapidly to baseline level within 24h. Dasatinib (1 mg/kg) resulted in little inhibition. In PBMCs, a similar time course and extent of phospho-SRC[pY418] inhibition was observed. Inhibition of phospho-SRC[pY418] in vivo appeared to correlate with the preclinical in vivo efficacy and PK profiles of dasatinib in mice., Conclusions: Phospho-SRC[pY418] may potentially be used as a biomarker to enable assessment of target inhibition in clinical studies exploring dasatinib antitumor activity.

SPRYCEL (dasatinib, BMS-354825; Bristol-Myers Squibb, Princeton, NJ), a multiple kinase inhibitor, is currently approved to treat chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia tumors in patients who are resistant or intolerant to imatinib mesylate (Gleevec; Novartis, Basel, Switzerland). After a 100-mg single p.o. dose of [(14)C]dasatinib to healthy volunteers, the radioactivity was rapidly absorbed (T(max) approximately 0.5 h). Both dasatinib and total radioactivity (TRA) plasma concentrations decreased rapidly with elimination half-life values of <4 h. Dasatinib was the major drug-related component in human plasma. At 2 h, dasatinib accounted for 25% of the TRA in plasma, suggesting that metabolites contributed significantly to the total drug-related component. There were many circulating metabolites detected that included hydroxylated metabolites (M20 and M24), an N-dealkylated metabolite (M4), an N-oxide (M5), an acid metabolite (M6), glucuronide conjugates (M8a,b), and products of further metabolism of these primary metabolites. Most of the administered radioactivity was eliminated in the feces (85%). Urine recovery accounted for <4% of the dose. Dasatinib accounted for <1 and 19% of the dose in urine and feces, respectively, suggesting that dasatinib was well absorbed after p.o. administration and extensively metabolized before being eliminated from the body. The exposures of pharmacologically active metabolites M4, M5, M6, M20, and M24 in patients, along with their cell-based IC(50) for Src and Bcr-Abl kinase inhibition, suggested that these metabolites were not expected to contribute significantly toward in vivo activity.

Molluscum contagiosum and warts are two very common viral-induced diseases of childhood. We report our 1-year experience with intralesional candida antigen therapy for both warts and molluscum contagiosum. A retrospective chart review was performed and a total of 217 patients were identified. Follow-up was obtained either through clinic visits or telephone interviews for 25/47 molluscum patients and 55/170 wart patients. Of the molluscum patients with follow-up, 14/25 (56%) had complete resolution, 7/25 (28%) had partial clearing, and 4/25 (16%) had no improvement. For the wart patients with follow-up, 48/55 (87%) had complete resolution, 3/55 (6%) had partial clearing, and 4/55 (7%) had no improvement. It is important to note that our clearance rate may be overestimated, as many patients were also treated concurrently with liquid nitrogen or other therapies. All wart and molluscum patients experienced some discomfort at the time of injection, but no serious side effects were reported. Our experience suggests intralesional candida antigen may represent a treatment option for warts and molluscum contagiosum that is safe and effective.

Ixabepilone (BMS-247550) is a semi-synthetic, microtubule stabilizing epothilone B analogue which is more potent than taxanes and has displayed activity in taxane-resistant patients. The human plasma pharmacokinetics of ixabepilone have been described. However, the excretory pathways and contribution of metabolism to ixabepilone elimination have not been determined. To investigate the elimination pathways of ixabepilone we initiated a mass balance study in cancer patients. Due to autoradiolysis, ixabepilone proved to be very unstable when labeled with conventional [14C]-levels (100 microCi in a typical human radio-tracer study). This necessitated the use of much lower levels of [14C]-labeling and an ultra-sensitive detection method, Accelerator Mass Spectrometry (AMS). Eight patients with advanced cancer (3 males, 5 females; median age 54.5 y; performance status 0-2) received an intravenous dose of 70 mg, 80 nCi of [14C]ixabepilone over 3 h. Plasma, urine and faeces were collected up to 7 days after administration and total radioactivity (TRA) was determined using AMS. Ixabepilone in plasma and urine was quantitated using a validated LC-MS/MS method. Mean recovery of ixabepilone-derived radioactivity was 77.3% of dose. Fecal excretion was 52.2% and urinary excretion was 25.1%. Only a minor part of TRA is accounted for by unchanged ixabepilone in both plasma and urine, which indicates that metabolism is a major elimination mechanism for this drug. Future studies should focus on structural elucidation of ixabepilone metabolites and characterization of their activities.

Background: Infectious mononucleosis (IM) commonly triggers a protracted postinfective fatigue syndrome (PIFS) of unknown pathogenesis., Methods: Seven subjects with PIFS with 6 or more months of disabling symptoms and 8 matched control subjects who had recovered promptly from documented IM were studied. The expression of 30,000 genes was examined in the peripheral blood by microarray analysis in 65 longitudinally collected samples. Gene expression patterns associated with PIFS were sought by correlation with symptom factor scores., Results: Differential expression of 733 genes was identified when samples collected early during the illness and at the late (recovered) time point were compared. Of these genes, 234 were found to be significantly correlated with the reported severity of the fatigue symptom factor, and 180 were found to be correlated with the musculoskeletal pain symptom factor. Validation by analysis of the longitudinal expression pattern revealed 35 genes for which changes in expression were consistent with the illness course. These genes included several that are involved in signal transduction pathways, metal ion binding, and ion channel activity., Conclusions: Gene expression correlates of the cardinal symptoms of PIFS after IM have been identified. Further studies of these gene products may help to elucidate the pathogenesis of PIFS.

Objective: A schema was recently proposed for assessing the levels of evidence for surrogate validity that included 4 domains: Target, Study Design, Statistical Strength, and Penalties. This report examines one component of the schema. It surveys the literature on methods of statistical validation of surrogate markers and compares these methods head-to-head using simulated datasets., Methods: Simulated datasets (continuous, multivariate normal) were generated to capture 3 possible relationships of surrogate (S) and true (T) outcome (none, weakly positive, strongly positive) each applied to 4 treatment effects (effect on both surrogate and true outcome, effect on neither, effect on surrogate only, and effect on true outcome only). These datasets were analyzed using single and multitrial statistical approaches, and the results were provided to participants for discussion., Results: The multitrial surrogate threshold effect seemed to capture best the requirement that surrogate validation is demonstrated by a treatment-associated change in the surrogate predicting a treatment-associated change in the outcome., Conclusion: There was general agreement that neither a single trial nor any of the single trial statistical methods was adequate to establish surrogate validity. These exercises also showed that summary statistics developed specifically to establish surrogate validity, such as the proportion of the effect explained, were problematic. A sizable statistical research agenda remains, which includes investigating the additional advantage obtained with modeling subject-level data compared to modeling with only trial-level data; and developing and testing multitrial statistical approaches robust to settings with only a few trials.

Objective: There are clear advantages to using biomarkers and surrogate endpoints, but concerns about clinical and statistical validity and systematic methods to evaluate these aspects hinder their efficient application. Our objective was to review the literature on biomarkers and surrogates to develop a hierarchical schema that systematically evaluates and ranks the surrogacy status of biomarkers and surrogates; and to obtain feedback from stakeholders., Methods: After a systematic search of Medline and Embase on biomarkers, surrogate (outcomes, endpoints, markers, indicators), intermediate endpoints, and leading indicators, a quantitative surrogate validation schema was developed and subsequently evaluated at a stakeholder workshop., Results: The search identified several classification schema and definitions. Components of these were incorporated into a new quantitative surrogate validation level of evidence schema that evaluates biomarkers along 4 domains: Target, Study Design, Statistical Strength, and Penalties. Scores derived from 3 domains the Target that the marker is being substituted for, the Design of the (best) evidence, and the Statistical strength are additive. Penalties are then applied if there is serious counterevidence. A total score (0 to 15) determines the level of evidence, with Level 1 the strongest and Level 5 the weakest. It was proposed that the term "surrogate" be restricted to markers attaining Levels 1 or 2 only. Most stakeholders agreed that this operationalization of the National Institutes of Health definitions of biomarker, surrogate endpoint, and clinical endpoint was useful., Conclusion: Further development and application of this schema provides incentives and guidance for effective biomarker and surrogate endpoint research, and more efficient drug discovery, development, and approval.

Hypotheses about the mechanisms of action by which a treatment affects a clinical outcome may prompt consideration of an alternative outcome as a potential surrogate. In many cases, due to costs or other factors, the candidate for surrogacy will only be measured for patients randomized to a substudy within the main trial. In this situation, the substudy patients provide information about links between the true and surrogate outcomes and the treatment, and these links can be exploited, using methods for handling missing covariates, to allow available information for patients not in the substudy to be incorporated into the analysis. The increased precision with which the treatment effect can be estimated using these methods, compared with using substudy data alone, in turn allows more precise estimates of measures of surrogacy. This paper reviews and compares some methods for handling missing covariate data and applies the methodology to a large heart attack trial, in order to investigate the properties of four measures for assessing the extent to which early response to thrombolytic therapy, as measured by an improvement in coronary blood flow, can be regarded as a surrogate for 30-day survival following heart attack. Design issues for substudies intended to assess treatment mechanisms are also considered. In particular, we consider how the precision of surrogate measures varies with the size of the substudy relative to the main trial. The results suggest that for reasonable surrogates, substudies substantially smaller than the main study can extract most of the available information regarding surrogacy.

Purpose: To determine whether BMS-275291, a broad-spectrum matrix metalloproteinase inhibitor (MMPI), added to systemic chemotherapy improved survival in advanced non-small-cell lung cancer (NSCLC). In early phase studies, BMS- 275291 was not associated with dose-limiting joint toxicity seen with other MMPIs., Patients and Methods: Chemotherapy-naive patients with stage IIIB/IV NSCLC, performance status (PS) 0 to 2, and adequate organ function were eligible. All patients received paclitaxel 200 mg/m2 plus carboplatin (area under the curve, 6 mg/mL-min) intravenously every 21 days for up to 8 cycles, and were randomly assigned to receive BMS-275291, 1,200 mg orally daily, or placebo until disease progression. The primary study end point was survival (OS); secondary end points included progression-free survival (PFS), response rates (RR), toxicity, and quality of life., Results: From 2000 to 2002, 774 patients were randomly assigned. Pretreatment characteristics were well balanced between arms: median age, 61 years; male sex, 73%; stage IV, 79%; PS 0 to 1, 88%. Interim safety analysis revealed no survival advantage and increased toxicity in the experimental arm, and study treatment was stopped. Median OS, PFS and RR in the final analysis in the BMS-275291 arm were 8.6 months, 4.9 months, and 25.8% respectively, and in the control arm 9.2 months, 5.3 months, 33.7%. Toxicity was significantly higher in the BMS-275291 arm, including flu-like symptoms, rash, hypersensitivity reactions (8.6% v 2.4%), and febrile neutropenia (9.7% v 5.5%)., Conclusion: BMS-275291 added to chemotherapy increases toxicity and does not improve survival in advanced NSCLC.

Objective: The platelet-derived growth factor (PDGF) family consists of four members, PDGF A, PDGF B, and 2 new members, PDGF C and PDGF D, which signal through the alpha and beta PDGF receptor (PDGFR) tyrosine kinases. This study was performed to determine the receptor specificity and cellular expression profile of PDGF C., Methods and Results: PDGF C growth factor domain (GFD) was shown to preferentially bind and activate alpha PDGFR and activate beta PDGFR when it is co-expressed with alpha PDGFR through heterodimer formation. An investigation of PDGF C mRNA and protein expression revealed that during mouse fetal development, PDGF C was expressed in the mesonephric mesenchyme, prefusion skeletal muscle, cardiac myoblasts, and in visceral and vascular smooth muscle, whereas in adult human tissues expression was largely restricted to smooth muscle. Microarray analysis of various cell types showed PDGF C expression in vascular smooth muscle cells, renal mesangial cells, and platelets. PDGF C mRNA expression in platelets was confirmed by real-time polymerase chain reaction, and PDGF C protein was localized in alpha granules by immuno-gold electron microscopy. Western blot analysis of platelets identified 55-kDa and 80-kDa PDGF C isoforms that were secreted on platelet activation., Conclusions: Taken together, our results demonstrated for the first time to our knowledge that like PDGF A and B, PDGF C is likely to play a role in platelet biology.

Purpose: This pilot trial was performed to evaluate the safety, pharmacokinetics and feasibility of incorporating BMS-275291, a matrix metalloproteinase inhibitor (MMPI), into adjuvant breast cancer therapy., Experimental Design: Patients with stage I (T1c)-IIIA breast cancer were eligible if planned adjuvant therapy consisted of either tamoxifen alone, doxorubicin + cyclophosphamide every 21 days for four cycles (AC), or AC followed by paclitaxel every 21 days for 4 cycles (AC>T). Patients were stratified by planned adjuvant therapy and randomized (2:1 ratio) to BMS-275291 (1200 mg/day) or matched placebo for 1 year., Results: Seventy-two patients were recruited from March 2001 to July 2002. Grade >or=2 musculoskeletal toxicity, generally reversible arthralgia, was reported by 36.2% of patients receiving BMS-275291 compared with 16.7% of patients receiving placebo; difference = 19.5% (95% confidence interval: -0.06, 0.44; P = NS). Two patients receiving BMS-275291 developed palpable nodules along tendons. Grade >or=3 rash was reported by 8.5% of patients receiving BMS-275291 compared with 4.2% of patients receiving placebo; difference = 4.3% (95% confidence interval: -0.18, 0.3; P = NS). Overall, 33% of BMS-275291 patients and 21% of placebo patients discontinued treatment due to adverse events. BMS-275291 trough levels tended to decrease over time; 9 of 47 (19%) had >or=50% of trough concentrations > 124 ng/ml (IC(90) for matrix metalloproteinase-9)., Conclusions: The pattern of arthralgia in BMS-275291-treated patients was consistent with matrix metalloproteinase inhibitor toxicity. Although the differential incidence of arthralgia did not reach statistical significance, the trial was terminated. An adjuvant trial in this patient population is not feasible.

This paper discusses interim analysis for clinical trials where the primary endpoint is observed at a specific long-term follow-up time, but where repeated measures of the same outcome are also taken at earlier times. Methods are considered for improving the efficiency with which the long-term treatment difference is estimated, making use of information from shorter-term follow-up times. This approach to interim analysis has previously been studied for binary endpoints assessed at two time points during follow-up. Here we adapt and extend this methodology to include continuous endpoints assessed at an arbitrary number of follow-up times, making use of methods for analysing multivariate normal data subject to monotone missingness and unstructured mean and covariance relationships. The magnitude of efficiency gains obtained by using short-term measurements is considered, as well as how these gains depend on the number and timing of the short-term measurements. Sequential analysis of treatment differences is discussed, including the extent to which efficiency gains translate into reductions in the expected duration of a sequentially monitored trial. The methods are illustrated on a data set involving a placebo-controlled comparison of longitudinal cholesterol measurements., (Copyright 2003 John Wiley & Sons, Ltd.)