bluuebunny/crossref_metadata_2025 huggingface dataset:
Sickle Cell Crisis Leading to Extensive Necrosis in a Low-Grade Glioma and Masquerading High-Grade Lesion
Authors: Agrawal Amit , Balpande D.N. , Khan A. , Vagh S.J. , Shukla Samarth , Chopra Sumit
Published: December 2008

A 9-year-old female child presented with rapid neurological deterioration. Clinical features and imaging findings were suggestive of high-grade malignancy, and hematological investigations were suggestive of sickle cell trait. Histopathology showed features of low-grade malignancy and extensive intratumoral sickling. We hypothesize that the vicious cycle of hypoxia, sickling, thrombosis, ischemia and infarction resulted in the extensive tumor necrosis in the present case causing the initial symptoms and rapid deterioration in the condition of the patient.
Localization of Extratemporal Seizure with Noninvasive Dense-Array EEG
Authors: Holmes Mark D. , Brown Micah , Tucker Don M. , Saneto Russell P. , Miller Kai J. , Wig Gagan S. , Ojemann Jeffrey G.
Published: December 2008

A 13-year-old girl presented with refractory seizures since the age of 5 years. Clinical exam and MRI studies were normal. Ictal EEG discharges suggested possible left posterior quadrant distribution but were not well localized with standard methods. A seizure was recorded during 128-channel EEG video long-term monitoring prior to invasive recordings. Applying a source analysis method, seizure onset and propagation patterns were calculated and displayed on an MRI model. The onset was localized to the left inferior posterior occipital cortex, followed by propagation to the right, then left, posterior cerebral hemispheres, and finally to the left superior-medial parietal lobe. These patterns were replicated closely on subsequent invasive recordings. Surgery was based on intracranial findings and she is seizure-free 30 months after resection. Noninvasive dense-array EEG, used in conjunction with realistic source analysis methods, may have the potential to assist in localizing seizure onsets when standard methods fail.
Multiple Intracranial Aneurysms with Intraventricular Hemorrhage in a Child with Unilateral Fibromuscular Dysplasia of the Renal Artery
Authors: Park Dong-Hyuk , Kang Shin-Hyuk , Lim Dong-Jun , Kwon Taek-Hyun , Park Jung-Yul , Chung Yong-Gu , Lee Hoon-Kap
Published: December 2008

A rare case involving multiple intracranial aneurysms with intraventricular hemorrhage (IVH) in a child, accompanied by unilateral fibromuscular dysplasia (FMD) of the renal artery, is reported. A 12-year-old girl presented with secondary hypertension and fourth-ventricle IVH. Cerebral angiography showed multiple aneurysms in the anterior communicating artery, right posterior cerebral artery, and right superior cerebellar artery. Abdominal angiography revealed marked stenosis and dilatation of the left renal artery. Coil embolization of the intracranial aneurysms was successfully performed. Then, a left nephrectomy and autotransplantation were performed. At the time of discharge, she was in an almost normal neurological condition. The association between renal artery FMD and aneurysmal rupture is extremely rare. This case is the first report of multiple intracranial aneurysms with IVH treated successfully with coils in a child concomitant with FMD of the renal artery.
Sir Samuel Wilks (1824–1911): On Epilepsy
Authors: Pearce J.M.S.
Published: December 2008

Samuel Wilks was one of that remarkable era of great physicians and syndrome creators based at Guy’s Hospital in the mid 19th century. He made signal contributions to the concept that epilepsy derived from surface lesions affecting the cortex, as opposed to the medulla. After Locock, he was largely responsible for the general use of bromide – in his day the only effective anticonvulsant.
Apert Syndrome: The Current Role of Prenatal Ultrasound and Genetic Analysis in Diagnosis and Counselling
Authors: Athanasiadis A.P. , Zafrakas M. , Polychronou P. , Florentin-Arar L. , Papasozomenou P. , Norbury G. , Bontis J.N.
Published: December 2008

Apert syndrome is a rare congenital malformation syndrome characterized by the triad of cutaneous and progressive bony syndactyly, midfacial hypoplasia and craniosynostosis. Two missense mutations of the gene encoding the fibroblast growth factor receptor 2 (FGFR2) have been implicated in most cases. We report a case of Apert syndrome detected on prenatal ultrasound. Postnatal genetic analysis showed, for the first time, that the previously reported P253R mutation of the FGFR2 gene is also prevalent in southeast Europe. After prenatal sonographic detection of anomalies suggestive of Apert syndrome, parents should be counselled about prognosis and risk of recurrence, and the option of amniocentesis should be offered.
Skewed Matrilineal Genetic Composition in a Small Wild Chimpanzee Community
Authors: Shimada Makoto K. , Hayakawa Sachiko , Fujita Shiho , Sugiyama Yukimaru , Saitou Naruya
Published: December 2008

Maternal kinship is important in primate societies because it affects individual behaviour as well as the sustainability of populations. All members of the Bossou chimpanzee community are descended from 8 individuals (herein referred to as original adults) who were already adults or subadults when field observations were initiated in 1976 and whose genetic relationships were unknown. Sequencing of the control region on the maternally inherited mtDNA revealed that 4 (1 male and 3 females) of the 8 original adults shared an identical haplotype. We investigated the effects of the skewed distribution of mtDNA haplotypes on the following two outcomes. First, we demonstrated that the probability of mtDNA haplotype extinction would be increased under such a skewed composition in a small community. Second, the ratio of potential mating candidates to competitors is likely to decrease if chimpanzees become aware of maternal kinship and avoid incest. We estimated that the magnitude of the decrease in the ratio is 10 times greater in males than in females. Here we demonstrate a scenario in which this matrilineal skewness in a small community accelerates extinction of mtDNA haplotype, which will make it more difficult to find a suitable mate within the community.
Common Genetic Variants in
ANK2
Modulate QT Interval
Authors: Sedlacek Kamil , Stark Klaus , Cunha Shane R. , Pfeufer Arne , Weber Stefan , Berger Iris , Perz Siegfried , Kääb Stefan , Wichmann Hans-Erich , Mohler Peter J. , Hengstenberg Christian , Jeron Andreas
Published: December 2008

Background—

Spatial and timely variations in QT interval, even within its normal range, may underlie susceptibility to cardiac arrhythmias and sudden cardiac death. Given its important role in cardiac electrophysiology, we hypothesized that common genetic variation in ankyrin-B gene (
ANK2
) might modify QT interval length.

Methods and Results—

The study population consisted of 1188 participants of the World Health Organizational Multinational Monitoring of Trends and Determinants in Cardiovascular Disease (WHO MONICA) general population survey Cooperative Health Research in the Region of Augsburg (KORA S3). Corrected QT interval was calculated using population specific linear regression formulas. A total of 22 single-nucleotide polymorphisms in the genomic region of
ANK2
gene were genotyped using TaqMan technology. In a replication study, 6 single nucleotide polymorphisms were genotyped in 3890 individuals from a second population study (KORA S4). The rare variant of the single-nucleotide polymorphism rs6850768 (allele frequency, 0.28) significantly influenced duration of the QT interval, both in KORA S3 and KORA S4 populations. In homozygotes, the shortening of the QT interval was 3.79 ms (95% CI, 1.48 to 5.58;
P
=0.001 and
P
=0.0008 for log-additive and dominant model, respectively) in KORA S3 and 2.94 ms (95% CI, 1.11 to 4.77;
P
=0.001 and
P
=0.006 for log-additive and dominant genetic model, respectively) in KORA S4. A common 2-locus haplotype (rs11098171-rs6850768; population frequency, 28%) was associated with a QT interval difference of 2.85 ms (permutation;
P
=0.006) in KORA S3 and 1.23 ms (permutation;
P
=0.009) in KORA S4. Reverse transcription–polymerase chain reaction expression analysis of the human
ANK2
5′ genomic region in the human left ventricular tissue revealed 2 previously unidentified
ANK2
5′ exons in the proximity of the identified variants.

Conclusions—

Common genetic variants juxtaposed with novel exons in the distant 5′ genomic region of
ANK2
influence the QT interval length in the general population. These findings support the role of ankyrin-B in normal cardiac electric activity.
Mesoscale Convective Systems and Critical Clusters
Authors: Peters Ole , Neelin J. David , Nesbitt Stephen W.
Published: December 2008

Size distributions and other geometric properties of mesoscale convective systems (MCSs), identified as clusters of adjacent pixels exceeding a precipitation threshold in satellite radar images, are examined with respect to a recently identified critical range of water vapor. Satellite microwave estimates of column water vapor and precipitation show that the onset of convection and precipitation in the tropics can be described as a phase transition, where the rain rate and likelihood of rainfall suddenly increase as a function of water vapor. This is confirmed in Tropical Rainfall Measuring Mission radar data used here. Percolation theory suggests that cluster properties should be highly sensitive to changes in the density of occupied pixels, which here translates into a rainfall probability, which in turn sensitively depends on the water vapor. To confirm this, clusters are categorized by their prevalent water vapor. As expected, mean cluster size and radius of gyration strongly increase as the critical water vapor is approached from below. In the critical region one finds scale-free size distributions spanning several orders of magnitude. Large clusters are typically from the critical region: at low water vapor most clusters are small, and supercritical water vapor values are too rare to contribute much. The perimeter of the clusters confirms previous observations in satellite, field, and model data of robust nontrivial scaling. The well-known area–perimeter scaling is fully compatible with the quantitative prediction from the plausible null model of gradient percolation, where the accessible hull is a fractal object with dimension 4/3.
Projected Midlatitude Continental Summer Drying: North America versus Europe
Authors: Rowell David P.
Published: December 2008

A common signal in climate model projections is a decline in average summer rainfall over midlatitude continents due to anthropogenic warming. Most models suggest this rainfall decline will be less severe over North America than over Europe. This study aims to understand this difference in continental response and make inferences about its reliability. Data are primarily derived from a “perturbed physics” ensemble of models [Quantifying Uncertainty in Model Predictions project, subensemble S4 (QUMP-S4)] and are also compared with data from a multimodel ensemble [the Coupled Model Intercomparison Project phase 3 (CMIP3)]. A description of the uncertainty of predicted summer rainfall decline over both continents and its broad similarity between the two ensembles suggests the possibility that the QUMP-S4 ensemble may include many of the mechanisms that cause the differential continental response in the CMIP3 ensemble. Analysis of the QUMP-S4 mechanisms and their variability across the ensemble lead to the following conclusions. Over western North America, it is judged that the change in summer rainfall is more uncertain than models suggest, with a decline that could be either more or less severe than that over Europe. This is due to the western North American region’s dependence on uncertain modeling of high-elevation winter–spring surface hydrology. Over eastern North America, it seems likely that summer rainfall will decline. In particular, this decline is likely to be less severe than that over continental Europe since this difference primarily depends on reliable aspects of the models. However, a further, but speculative, conclusion is that these mechanisms could also lead to a larger increase in extreme rainfall events over eastern North America than over Europe.
Response to a Steady Poleward Outflow. Part I: The Linear, Quasigeostrophic Problem
Authors: Durland Theodore S. , Pedlosky Joseph , Spall Michael A.
Published: December 2008

The response of a zonal channel to a uniform, switched-on but subsequently steady poleward outflow is presented. An eastward coastal current with a Kelvin wave’s cross-shore structure is found to be generated instantly upon initiation of the outflow. The current is essentially in geostrophic balance everywhere except for the vicinity of the outflow channel mouth, where the streamlines must cross planetary vorticity contours to feed the current. The adjustment of this region generates a plume that propagates westward at Rossby wave speeds. The cross-shore structure of the plume varies with longitude, and at any given longitude it evolves with time. The authors show that the plume evolution can be understood both conceptually and quantitatively as the westward propagation of the Kelvin current’s meridional spectrum, with each spectral element propagating at its own Rossby wave group velocity.
Trait anxiety among Japanese massage practitioners with visual impairment: what is required in Japanese rehabilitation education?
Authors: Donoyama Nozomi , Munakata Tsunetsugu
Published: December 2008

This questionnaire-based study of Japanese massage practitioners with visual impairment ( n = 155, 126 males, 29 females, mean age = 41 years) found that measures of self-repression, helplessness and `daily hassles' were positively correlated to measures of trait anxiety. Also, trait anxiety was negatively associated with measures of self-esteem and perceived emotional support. Participants with moderate visual impairment (able to read print) showed significantly higher trait anxiety than those with severe visual impairment (those who read braille). Moreover, compared to sighted people in other medical professions, the participants in this study demonstrated higher levels of self-repression. Regarding onset of impairment, people with onset in adolescence had significantly higher self-repression scores than those with onset in adulthood. Overall, the results of this study are used to argue the importance of establishing social support systems in the workplace as well as incorporating psychological approaches with communication skills training in rehabilitation education for people with visual impairment.
Visual acuity impairment and vision-related quality of life: the Barbados Eye Studies
Authors: Wu Suh-Yuh , Nemesure Barbara , Hennis Anselm , Leske M. Cristina
Published: December 2008

In addition to clinical criteria, self-perceptions of vision-related functioning and well-being are recognized as important measures for characterizing the disability associated with visual impairment. This report assessed the impact of visual impairment in a subset of the African-origin participants of the population-based Barbados Eye Studies, using the US National Eye Institute's 25-item Visual Functioning Questionnaire (NEI-VFQ-25). Visual impairment was associated with significantly (P ≤ 0.01) lower VFQ scores in multidimensional aspects of vision-related quality of life (QOL), including vision-related activities and psychosocial functioning. Adjusted mean composite scores were 12 points (95% confidence interval: 9.5, 14.5) and 31 points (26.7, 34.6) lower for low vision and blindness, respectively, compared with no impairment, and 13 points (7.7, 17.6) lower for visual impairment not correctable, compared with correctable with refraction. In this population with high rates of visual disability, impaired visual acuity adversely impacted the self-perceived QOL, as measured by this instrument.
Spelling performance of visually impaired adults
Authors: Papadopoulos Konstantinos S. , Arvaniti Evmorfia K. , Dimitriadi Despina I. , Gkoutsioudi Vasiliki G. , Zantali Christina I.
Published: December 2008

Visual processes undoubtedly play an important role in print reading as well as in spelling. In the present study we intend to compare the spelling performance of visually impaired individuals (both individuals who are blind and individuals with low vision) with that of their fully sighted peers. An analysis of errors (misspelled words and spelling mistakes) was conducted. The influence of certain factors — such as gender, age, educational level and the most common medium of reading — over spelling performance was also assessed. Our results suggest that the severity of the visual disability appears to have a negative effect on the spelling performance of visually impaired adults, although the number of errors declines as the subject's level of education increases. Blind or severely visually impaired subjects who used braille frequently seem to perform better at spelling compared to those who rely on other media. Adults with low vision who use magnifying lenses frequently seem to make more spelling mistakes than those who use braille, large print, CCTV or the computer (screen-reading or screen-magnification software).
Test architecture, test retrofit
Authors: Fulcher Glenn , Davidson Fred
Published: December 2008

Just like buildings, tests are designed and built for specific purposes, people, and uses. However, both buildings and tests grow and change over time as the needs of their users change. Sometimes, they are also both used for purposes other than those intended in the original designs. This paper explores architecture as a metaphor for language test development. Firstly, it describes test purpose and use, and how this affects test design. Secondly, it describes and illustrates the layers of test architecture and design. Thirdly, it discusses the concept of test retrofit, which is the process of altering the test after it has been put into operational use. We argue that there are two types of test retrofit: an upgrade and a change. Each type of retrofit implies changes to layers of the test architecture which must be articulated for a validity argument to be constructed and evaluated. As is true in architecture, we argue that a failure to be explicit about retrofit seriously limits validity claims and clouds issues surrounding the intended effect of the test upon users.
Serum 25-Hydroxyvitamin D Concentration and Cognitive Impairment
Authors: Llewellyn David J. , Langa Kenneth M. , Lang Iain A.
Published: December 2008

Vitamin D may be of interest in the prevention of cognitive impairment, though previous findings are inconclusive. Participants were 1766 adults aged 65 years and older from the Health Survey for England 2000, a nationally representative population-based study. Cognitive impairment was assessed using the Abbreviated Mental Test Score. The cross-sectional relation of serum 25-hydroxyvitamin D quartiles to cognitive impairment was modeled using logistic regression. In all, 212 participants (12%) were cognitively impaired. Odds ratios (95% confidence intervals) for cognitive impairment in the first (8-30 nmol/L), second (31-44 nmol/L), and third (45-65 nmol/L) quartiles of serum 25-hydroxyvitamin D compared with the fourth (66-170 nmol/L) were 2.3 (1.4-3.8), 1.4 (0.8-2.4), and 1.1 (0.6-1.9), after adjustment for age, sex, education, ethnicity, season of testing, and additional risk factors for cognitive impairment (P for linear trend = .001). Our data suggest low serum 25-hydroxyvitamin D is associated with increased odds of cognitive impairment.
Association of ACE I/D Gene Polymorphism With Vascular Dementia: A Meta-Analysis
Authors: Hua Liu  , Ming Liu  , Wei Li  , Bo Wu  , Zhang Shi-hong , Yuan Fang  , Yi Wang
Published: December 2008

Background: Vascular dementia is the second common cause of dementia, only second to Alzheimer's disease in later life, and has a greater mortality risk than Alzheimer's disease among the elderly population group. The angiotensin-converting enzyme insertion/deletion polymorphism as a risk factor in vascular dementia has been suggested, but direct evidence from genetic association studies remain inconclusive. We performed a meta-analysis pooling data from all relevant studies in order to determine the effect of the insertion/deletion polymorphism on the vascular dementia.

Methods: We applied a random-effects model or fixed-effects model to combine odds ratio and 95% confidence intervals. Q statistic was used to evaluate the homogeneity, and Egger's test and Funnel plot were used to assess publication bias.

Results: A total of 10 studies were included worldwide. Publication bias was not observed. There was no evidence of the association of angiotensin-converting enzyme insertion/deletion polymorphism with the vascular dementia in general or in the Asian populations or in the Caucasian populations. Conclusions: The angiotensin-converting enzyme insertion/deletion polymorphism might be neutral to vascular dementia.
Association of programmed cell death 1 polymorphisms and systemic lupus erythematosus: a meta-analysis
Authors: Lee YH , Woo JH , Choi SJ , Ji JD , Song GG
Published: December 2008

Programmed cell death 1 ( PDCD1 or PD1) polymorphisms have been inconsistently reported to be associated with systemic lupus erythematosus (SLE). The aim of this study was to explore whether the PDCD1 polymorphisms confer a susceptibility to SLE and lupus nephritis (LN). We conducted a meta-analysis on the association of PDCD1 polymorphisms with SLE in overall and specific ethnic populations. A total of 15 separate comparisons were included in this meta-analysis consisting of nine Europeans, two Latin Americans, two Africans, one Asian and one unknown participant. In subgroup analysis, the PD1.3A allele was significantly associated with SLE in Latin Americans (OR = 3.073, 95% CI = 1.416–6.461, P = 0.003), but not in patients of European and African decent. The PD1.3A allele was a risk factor for LN in European descendants (OR = 2.207, 95% CI = 1.488–3.467, P < 0.001). The PD1.5C allele was a risk factor for SLE in Europeans (OR = 1.297, 95% CI = 1.024–1.643, P = 0.031). In conclusion, this meta-analysis demonstrated an association of the PD1.3A allele with LN in European and SLE in Latin-American populations. Furthermore, the PD1.5C allele was associated with SLE susceptibility in Europeans.
Thrombotic thrombocytopenic purpura in systemic lupus erythematosus: risk factors and clinical outcome: a single centre study
Authors: Kwok SK , Ju JH , Cho CS , Kim HY , Park SH
Published: December 2008

The study was undertaken to investigate clinical characteristics of thrombotic thrombocytopenic purpura (TTP) in patients with SLE and to determine risk factors and clinical outcome of TTP in patients with SLE. Among the 1203 patients with SLE admitted to catholic medical centre of the catholic university of Korea from January 1990 to December 2006, 26 patients with SLE were found to admit with TTP. TTP was defined if microangiopathic haemolytic anaemia, thrombocytopenia and negative Coombs’ test were present and when at least one of the following signs was noted: renal impairment, neurologic deficit or fever. Eighty-seven patients with SLE who admitted with other manifestations, matched for age and sex, were included as disease controls. Data were retrospectively analysed based on medical records. There were no significant demographic characteristics between SLE patients with TTP and those with other manifestations. Multivariate analysis showed that independent risk factors for the development of TTP included high SLE disease activity index score (SLEDAI > 10, P = 0.006) and coexisting nephritis ( P = 0.004). Among the 26 SLE patients with TTP, 12 died during admission period (in-hospital mortality rate: 46.1%). SLE patients with infection or neurologic manifestations had higher mortality rates. Multivariate analysis showed that infection is the only independent risk factor for mortality in SLE patients with TTP ( P = 0.035). Patients with SLE who are in the active stage or who have renal involvement have the increased risk for TTP. Development of TTP in patients with SLE can be fatal. Therefore, intensive therapy will be needed especially in the presence of infection.
Effects of rituximab on resistant SLE disease including lung involvement
Authors: Reynolds JA , Toescu V , Yee CS , Prabu A , Situnayake D , Gordon C
Published: December 2008

We present a retrospective review of 11 patients with refractory systemic lupus erythematosus (SLE) treated with rituximab after failing corticosteroids and at least one other immunosuppressive drug. We measured clinical response using the Classic British Isles Lupus Assessment Group (BILAG) index, serum complement and reduction in maintenance prednisolone dose. B cells were measured using flow cytometry, and lung function testing was used to assess severe pulmonary disease (three patients). The median patient age was 42 years (range, 25–64) with median disease duration 6 years (range, 2–12). In all, 10 of 11 patients responded initially, with median global BILAG reduction of 7.5 at 6 months ( P = 0.007), with loss of all A and B scores by 7 months. Rituximab treatment was associated with normalisation of complement (C3 P = 0.008, C4 P = 0.018) and reduction in steroid requirement, median reduction 15 mg/day ( P = 0.036). In 9 of 10 patients who responded, all other immunosuppressants were stopped. There was no significant difference in anti-dsDNA antibody titres in these responders, but they were negative or had low titres at baseline. B-cell depletion continued for median 4 months (range, 2–9), and disease flare occurred at a median 6.6 months (range, 1.5–23) and was preceded by B-cell recovery in all but two patients. Rituximab was beneficial in refractory SLE including severe neurological and cardiorespiratory disease by inducing disease remission, allowing withdrawal of other agents and reduction in steroid requirement. Rituximab appeared to stabilise and possibly improve progressive lung disease.
Towards a Practice of Respecting the In-between: Condition Sine Qua Non of Living Together Peacefully
Authors: Mulder Anne-Claire
Published: December 2008

Living together peacefully in a world of differences asks for a practice of respecting the irreducible difference of the other. Acknowledging this `not-me' of the other subject generates an in-between: a space/time between subjects that cannot be transgressed other than by violence. Following Irigaray, I argue that this `in-between' comes about through the passion of wonder, a being touched in the flesh in the encounter with the other, which opens the subject to him/herself and to the other. To perceive this touch asks for a life-style directed at keeping open and sensitizing the sensibilities of the senses, so that the subject's aesthesis or awareness for the perceptions of the sensible flesh and of its reactions to the other is heightened. Key-element in this aesthetics is the practice of breathing. It enables the subject to remain rooted in him/or herself and open to the other: generating and respecting the in-between between them.
A Vital Human Need
Authors: Ikäheimo Heikki
Published: December 2008

Why is recognition of such an importance for humans? Why should lack of recognition motivate people to fight or work for recognition? In this article, I first discuss shortly Axel Honneth's somewhat psychologizing strategy for answering these questions, and suggest that the psychological harms of lack of recognition pointed out by Honneth are neither sufficient nor necessary for motivation to fight or work for recognition to arise. According to the alternative that I then spell out, recognition and lack of it are so intimately intertwined with some of the most fundamental and intuitively appealing facts about what it is to be a person in a full-fledged sense — arguably in any culture — that there are reasons to be optimistic about a more or less universal existence of latent motivation to fight or work for more or more equal recognition.
Demanding Recognition
Authors: McBride Cillian
Published: December 2008

This article argues that we must distinguish between two distinct currents in the politics of recognition, one centred on demands for equal respect which is consistent with liberal egalitarianism, and one which centres on demands for esteem made on behalf of particular groups which is at odds with egalitarian aims. A variety of claims associated with the politics of recognition are assessed and it is argued that these are readily accommodated within contemporary liberal egalitarian theory. It is argued that, pace Taylor, much of what passes for `identity' or recognition politics is driven by demands for equal respect, not by demands for esteem/affirmation. Given the inherently hierarchical nature of esteem recognition, no liberal state can consistently grant such recognition. Furthermore, these demands pose the risk of intensifying intergroup competition and chauvinism. Esteem recognition is valuable for individuals, but plays a problematic role for egalitarian politics.
Acute Myeloid Leukemia: The Challenge of Capturing Disease Variety
Authors: Löwenberg Bob
Published: December 2008

The difference between success and failure of treatment of acute myeloid leukemia (AML) is largely determined by genotypic leukemia-specific differences among patients. The diversity of AML genotypes result from somatic genetic alterations settling down in succession in an individual’s leukemia clone during the development of the disease. Gene mutations, gene expression abnormalities and other molecular alterations (e.g., microRNA variations) affect critical functions in AML cells, and may exert profound effects on the therapeutic response and outcome of the disease. Prototypes of common clinically significant gene aberrations involve transcription factors, signaling molecules and growth factor receptors. The expanding knowledge in this area allowing for risk stratified therapy decisions and the development of targeted drug therapy, is becoming an increasingly important part of the modern individualized clinical management of AML. This chapter highlights recent insights into the diagnostic, prognostic and therapeutic impact of chromosomal (e.g., the so-called monosomal karyotype) as well as particular genomic abnormalities, and presents examples of decision algorithms for individualized therapy.
Recognizing and Managing Chronic Graft-Versus-Host Disease
Authors: Lee Stephanie J. , Flowers Mary E. D.
Published: December 2008

Chronic graft-versus-host disease (GVHD) is an immune-mediated disorder that occurs frequently after allogeneic hematopoietic cell transplantation (HCT). Most cases are diagnosed within the first year at a median of 4 to 6 months after HCT, but 5–10% of cases are initially diagnosed beyond the first post-transplant year. Chronic GVHD most often involves the skin and mouth, but almost any other organ system can be involved. Correct diagnosis is critical so that appropriate therapy can be started promptly to minimize symptoms and prevent irreversible organ damage. Initial treatment should be with cortico-steroid-based therapy. Optimal secondary treatment as not been established, although a large number of agents may provide benefits. A 2004 NIH conference focused on development of consensus criteria for chronic GVHD. Six papers published in 2005 and 2006 propose consensus definitions for chronic GVHD diagnosis and scoring, pathology, biomarkers, response criteria, supportive care and design of clinical trials.

This review will focus on common clinical presentations and principles for managing chronic GVHD. The most frequently used secondary therapies and ongoing trials are summarized. New concepts from the NIH consensus conference are discussed.
Old and New Cancers after Hematopoietic-Cell Transplantation
Authors: Majhail Navneet S.
Published: December 2008

Relapse of primary disease and occurrence of new cancers can cause significant morbidity and mortality in recipients of autologous and allogeneic hematopoietic-cell transplantation (HCT). Treatment options for relapse are generally limited and can include disease-specific chemotherapy or targeted therapy. Additional relapse-directed therapies that are available for allogeneic HCT recipients include withdrawal of immunosuppression and donor lymphocyte infusion. Selected patients can be offered a second transplant procedure. Newer strategies to eliminate minimal residual disease and, in allogeneic HCT recipients, to augment the graft-versus-tumor effect are needed for patients who are at high risk for relapse after HCT. Second cancers after HCT include post-transplant lymphoproliferative disorder, hematologic malignancies and new solid cancers. The incidence of second solid cancers continues to rise without a plateau with increasing follow up of HCT survivors. Secondary myelodysplastic syndrome and acute leukemia are almost exclusively seen in autologous HCT recipients while post-transplant lymphoproliferative disorders complicate recipients of allogeneic HCT. Appropriate screening evaluations should be performed in HCT survivors to facilitate early detection and treatment of second cancers.
Mechanisms of Vasculopathy in Sickle Cell Disease and Thalassemia
Authors: Morris Claudia R.
Published: December 2008

Many mechanisms contribute to the complex pathophysiology of sickle cell disease (SCD), with dysfunction of the vascular endothelium as a unifying theme. Specifically, hemolysis-associated low arginine and nitric oxide (NO) bioavailability, amplified by NO synthase uncoupling, elevated arginase activity, superoxide production, oxidative stress, accumulation of arginine analogs such as asymmetric dimethylarginine, ischemia-reperfusion injury, inflammation, apolipoprotein A-1 depletion, and a hypercoagulable state are significant mechanisms contributing to endothelial dysfunction. Genetic polymorphisms also influence disease severity. Clearly the variable spectrum of disease is the consequence of multiple events and genetic susceptibility that go beyond the occurrence of a single amino acid substitution in the beta globin chain of hemoglobin. Recent studies begin to demonstrate overlap among these seemingly unrelated processes. Impaired NO bioavailability represents the central feature of endothelial dysfunction, and is a common denominator in the pathogenesis of vasculopathy in SCD. The consequences of decreased NO bioavailability include endothelial cell activation, upregulation of the potent vasoconstrictor endothelin-1, vasoconstriction, platelet activation, increased tissue factor, and activation of coagulation, all of which ultimately translate into the clinical manifestations of SCD. Evidence supporting vasculopathy subphenotypes in SCD, including pulmonary hypertension, priapism, cutaneous leg ulceration, and stroke, will be reviewed and relevance to other hemolytic disorders including the thalassemia syndromes will be considered.
New Strategies for the Optimal Use of Platelet Transfusions
Authors: Blajchman Morris A. , Slichter Sherrill J. , Heddle Nancy M. , Murphy Michael F.
Published: December 2008

Patients with severe thrombocytopenia are presumed to be at increased risk for bleeding, and consequently it has been standard practice for the past four decades to give allogeneic platelet transfusions to severely thrombocytopenic patients as supportive care. Platelet transfusions may be given either prophylactically to reduce the risk of bleeding, in the absence of clinical hemorrhage (prophylactic transfusions), or to control active bleeding when present (therapeutic transfusions). While no one would argue with the need for platelet transfusions in the face of severe bleeding, important questions remain about what constitutes clinically significant bleeding and whether a strategy of prophylactic platelet transfusions is effective in reducing the risk of bleeding in clinically stable patients. It is now uncommon for patients undergoing intensive chemotherapy or bone marrow transplantation to die of hemorrhage, but it is open to debate as to what degree platelet transfusions have been responsible for this change in outcome, given the many other advances in other aspects of supportive care.

If a prophylactic strategy is followed, the optimal transfusion trigger or quantity of platelets to be transfused prophylactically per transfusion episode needs to be addressed in adequately powered clinical trials, but these remain highly controversial issues. This is because, until recently, there have been few high-quality, prospective, randomized clinical trial (RCT) data for evaluating the relative effects of different platelet transfusion regimens or platelet doses on clinical outcomes. Moreover, most of these RCTs have not used bleeding as the primary outcome measure. Two such studies on platelet dose have now been undertaken, the PLADO (Prophylactic PLAtelet DOse) and the SToP (Strategies for the Transfusion of Platelets) trials. Data from these RCTs are not contained in this overview, as these data have not yet been completely analyzed or submitted for peer review publication.

In addition to the above, several recent observational studies have raised the possibility that there is not a clear association between the occurrence of a major clinical bleeding episode and the platelet count in thrombocytopenic patients. Such findings have led to the questioning of the efficacy of prophylactic platelet transfusions in all clinically stable patients, and whether a policy of therapeutic transfusions used only when patients have clinical bleeding might be as effective and safe for selected patients. At least two RCTs evaluating the relative value of prophylactic versus therapeutic platelet transfusions have been initiated in thrombocytopenic patients with hematological malignancies. One such study, known as the TOPPS (Trial of Prophylactic Platelets Study) study, is currently underway in the U.K.
Thrombophilia States and Markers of Coagulation Activation in the Prediction of Pediatric Venous Thromboembolic Outcomes: A Comparative Analysis with Respect to Adult Evidence
Authors: Goldenberg Neil A.
Published: December 2008

Venous thromboembolism (VTE) in children is an important clinical concern for which risk factors include clinical conditions that incite venous stasis, endothelial damage, or thrombophilia (i.e., hypercoagulability) states. Acquired thrombophilia and markers of coagulation activation are common in pediatric VTE, while potent genetic thrombophilia states are less frequently encountered; nevertheless, the latter are more likely to present in the pediatric age than in older adulthood. Sequelae of VTE and its treatment in childhood survivors include bleeding, persistent or progressive thrombosis, recurrent VTE, and (when venous return from a limb is affected) the development of post-thrombotic syndrome (PTS). The focus of the present review is to discuss the role of tests of thrombophilia and coagulation activation as key predictors of outcome in this disease. Based upon this understanding, coupled with existing knowledge of clinical prognostic factors, new risk-stratified approaches of antithrombotic therapy have emerged for clinical investigation in the field of pediatric VTE.
New Issues in Oral Anticoagulants
Authors: Francis Charles W.
Published: December 2008

Polymorphisms in CYP2C9, a critical cytochrome P-450 enzyme in the metabolism of warfarin, alters its clearance and affects dosing. CYP*1 has higher activity than either the *2 or *3 variants, and patients with the *2 or *3 variants require a lower dose. VKORC1 is the enzyme inhibited by warfarin, and its levels are affected by several polymorphisms that can be divided into high or low level haplotypes, and patients with high level haplotypes require higher warfarin doses. The use of algorithms for dosing that incorporate pharmacogenomic information perform better than those using clinical data alone. Considerable effort is ongoing to develop new oral anticoagulants as alternatives to warfarin, and three agents are in advanced development. Dabigatran is an oral direct thrombin inhibitor that has been compared with enoxaparin for prevention of VTE following hip or knee replacement. Based on non-inferiority results in European trials, it has now been approved for marketing in Europe. Phase III trials with a new oral Xa inhibitor, rivaroxaban, have been completed in hip or knee replacement, and rivaroxaban was superior to enoxaparin in prevention of VTE with no increase in bleeding complications. Phase III studies with apixaban, another oral Xa inhibitor, are in progress. These agents are also being evaluated in large studies for prevention of stroke in atrial fibrillation and for VTE treatment.
Novel Therapies and Role of Transplant in the Treatment of Peripheral T-Cell Lymphomas
Authors: Horwitz Steven M.
Published: December 2008

Peripheral T-cell lymphomas (PTCL) are an uncommon, heterogeneous group of non-Hodgkin lymphomas that carry a much poorer prognosis than their more common B-cell counterparts. The most commonly used treatment is CHOP or its variations. However, while the results with CHOP are inadequate, there is little compelling data to suggest a preferred alternate strategy. Many of these alternate strategies have been assembled from retrospective data, small case series, subset analyses, phase II studies and individual experience. The greatest experience with alternative treatments has been with the use of high-dose therapy as consolidation. These approaches are promising, but most of the studies are retrospective and include patients with diverse prognoses, making interpretation difficult. Preliminary results of prospective trials in PTCL are only recently being reported. Perhaps more exciting have been the increasing numbers of new therapies being studied for patients with PTCL. The activities of new drugs are being described in studies specifically for PTCL, and attempts at novel combinations are beginning.
Does Helicobacter pylori Eradication Therapy Result in a Platelet Count Improvement in Adults with Immune Thrombocytopenic Purpura Regardless of H pylori Infection?
Authors: Arnold Donald M. , Stasi Roberto
Published: December 2008

A 34-year-old male with a long history of immune thrombocytopenic purpura (ITP) presents to your office. His platelet count is 30 × 109/L and he is clinically stable with no bleeding symptoms. He has read that Helicobacter pylori eradication therapy may be effective for ITP and he asks you about this. You do not have access to reliable tests for H pylori infection (e.g., urea breath test), yet you wonder about the benefit of empiric eradication therapy for your patient.
Limited-Stage Disease: Optimal Use of Chemotherapy and Radiation Treatment
Authors: Radford John
Published: December 2008

In the early years of treatment for limited-stage Hodgkin lymphoma there was an understandable focus on disease elimination. This has been replaced by concerns about the amount and balance of different therapies and eventually, as cure rates improve, a desire to individualize management based on risk factors at presentation and response to initial treatment. In limited stage Hodgkin lymphoma, early success was obtained with wide field radiotherapy but later combined modality approaches were employed to overcome the problem of out of field radiotherapy relapses. The acute and delayed toxicity of alkylating agent based therapies led to their replacement with ABVD and concerns about the late toxicity of radiotherapy resulted in smaller field sizes being first assessed in clinical trial and later introduced into clinical practice. The current standard of care of 3 or 4 cycles of ABVD followed by involved-field radiotherapy in clinically staged patients is the culmination of years of work involving many thousands of patients taking part in clinical trials.

Our current focus is on the role of PET imaging and whether a response-adapted approach guided by PET can individualize therapy such that radiotherapy and its attendant late toxicity that impacts on future quality of life and survival can be avoided altogether in a subset of patients.
Primary Mediastinal B-Cell Lymphoma
Authors: Johnson Peter W.M. , Davies Andrew J.
Published: December 2008

Primary mediastinal B-cell lymphoma is a discrete clinicopathologic entity. Molecular analysis reveals it to be distinct from other types of large B-cell lymphoma, and retrospective analysis suggests that it may respond better to multi-agent chemotherapy regimens than to the more commonly used CHOP. The addition of rituximab may mitigate such differences, and may also diminish the role of consolidation radiotherapy, which is often used to treat residual mediastinal masses. For the future the role of FDG-PET scanning requires prospective examination, and it is hoped that this may allow the de-escalation of treatment if it can be shown to yield reliable prognostic information. The relative rarity of this type of lymphoma necessitates international collaboration in clinical trials, with a prospective clinicopathologic study, IELSG 26, already underway.
Molecular Determinants of Treatment Response in Acute Lymphoblastic Leukemia
Authors: Campana Dario
Published: December 2008

Treatment response in patients with acute lymphoblastic leukemia (ALL) is best assessed using assays for minimal residual disease (MRD). The degree of leukemia cytoreduction and MRD clearance is determined by the collective influence of multiple factors. Some of these variables are features of the leukemic cells, such as expression of genes that regulate their susceptibility to cytotoxic drugs and their propensity to undergo apoptosis. Gene profiles depend, in turn, on the cell of origin for leukemic transformation, the type of underlying genetic abnormalities and/or epigenetic regulatory mechanisms. Another set of variables is related to the host, such as age and polymorphisms in genes that metabolize drugs, which together with pharmacologic variables, such as drug pharmacodynamics and drug interactions, influence treatment response. Finally, the bone marrow microenvironment where leukemic cells reside can participate in the generation of drug resistance. Altogether, these variables determine treatment outcome in each patient. Full knowledge of the molecular features associated with treatment response is required for precise leukemia prognostication and monitoring, and can provide clues to useful targets for novel therapies.
The Treatment of Adults with Acute Lymphoblastic Leukemia
Authors: Fielding Adele
Published: December 2008

Despite the relatively low incidence of acute lymphoblastic leukemia (ALL) in adults, large national and international collaborations have recently improved our understanding of how to treat ALL in adults. This article documents and examines the current evidence base for a “state of the art” therapy in both Philadelphia chromosome–negative and –positive adult ALL. The article comments upon areas of therapeutic debate, such as the role of bone marrow transplantation. In particular, the controversial subject of whether the superior outcome seen in younger patients is predicated on disease biology or therapeutic strategy is examined closely. Promising approaches under development are also discussed.
Milestones and Monitoring in Patients with CML Treated with Imatinib
Authors: Deininger Michael W.
Published: December 2008

Imatinib is the therapeutic standard for newly diagnosed patients with chronic myeloid leukemia (CML). Recent updates of the IRIS trial, a study of standard-dose imatinib in newly diagnosed chronic-phase patients treated with 400 mg imatinib daily, suggest a stabilization of progression-free survival curves at a high level, implying that the majority of patients will do well on standard therapy. However, some 20% to 30% of patients will fail on imatinib and require alternative therapies. Identification of those patients likely to fail would be desirable to allow for more intensive therapy up front. After a brief overview of the history of CML, this paper will review current recommendations for staging of CML patients at diagnosis. Next, the various tests used to monitor their response to imatinib will be discussed in the context of the currently accepted criteria for imatinib failure and suboptimal response. Last, approaches to identify high-risk patients at diagnosis will be addressed.