bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular Pathways Regulating Cytoskeletal Organization and Morphological Changes in Migrating Neurons
Authors: Kawauchi Takeshi , Hoshino Mikio
Published: December 2007

Neuronal migration is a pivotal step for architectural and functional brain development. Migrating neurons exhibit various morphological changes, based on cytoskeletal organization. In addition to many genetic studies revealing the involvement of several cytoskeletal and signaling molecules in cortical neuronal migration (e.g. doublecortin, Lis1, Filamin A, cyclin-dependent kinase 5, Reelin and Dab1), cell biological studies and recently developed techniques, including in utero electroporation, have uncovered detailed functions of these molecules as well as novel molecules, such as Rho family GTPases, focal adhesion kinase, c-jun N-terminal kinase and p27kip1. In this review, we introduce the molecular pathways underlying cortical neuronal migration and morphological changes, with particular focus on recent findings for the regulatory mechanisms of actin cytoskeleton and microtubules.
Histogenetic Processes Leading to the Laminated Neocortex: Migration Is Only a Part of the Story
Authors: Caviness V.S. , Bhide P.G. , Nowakowski R.S.
Published: December 2007

The principal events of neocortical histogenesis were anticipated by work published prior to the 20th century. These were neuronal proliferation and migration and the complex events of cortical pattern formation leading to a laminated architecture where each layer is dominated by a principal neuronal class. Work that has followed has extended the knowledge of the workings of the proliferative epithelium, cellular mechanisms of migration and events through which cells are winnowed and then differentiate once their postmigratory positions are established. Work yet ahead will emphasize mechanisms that coordinate the molecular events that integrate proliferation and cell class specification in relation to the final neocortical neural system map.
Campath-1H Treatment of Multiple Sclerosis
Authors: Jones Joanne L. , Coles Alasdair J.
Published: December 2007

Campath-1H is a humanised monoclonal antibody that targets CD52, a cell surface protein expressed on lymphocytes, monocytes and eosinophils. A single dose of Campath-1H leads to a rapid and profound lymphopenia. Campath-1H has been used in Cambridge as an experimental treatment of multiple sclerosis for more than 15 years. Here, we summarise our clinical and laboratory findings, describing how this prototypical ‘bench to bedside’ therapy continues to inform basic science, revealing aspects of the pathogenesis of multiple sclerosis and autoimmunity.
Positive and Negative Implications of Tumor Necrosis Factor Neutralization for the Pathogenesis of Multiple Sclerosis
Authors: Taoufik E. , Tseveleki V. , Euagelidou M. , Emmanouil M. , Voulgari-Kokota A. , Haralambous S. , Probert L.
Published: December 2007

Multiple sclerosis (MS) is a progressive, presumably autoimmune, degenerative disease of the central nervous system (CNS). The mechanisms which trigger the disease are unknown, but the pathology of MS is caused by the host’s own immune system, which invades the CNS and attacks the myelin sheath that protects and insulates the axons of the nerve cells. Although this inflammatory assault selectively destroys myelin, it is believed that the neurological deficits of MS are rather the consequence of damage to axons, which occurs secondary to inflammation. The inflammatory mediators are generally secreted by myelin-specific, CD4+ T cells, CD8+ T cells, macrophages and activated glial cells and include a large number of cytokines, chemokines and other proinflammatory proteins.
Biomechanics of the Bat Limb Skeleton: Scaling, Material Properties and Mechanics
Authors: Swartz Sharon M. , Middleton Kevin M.
Published: December 2007

Background/Aims: Wing skeletons of bats are uniquely specialized for flight, reflecting both evolutionary history and the need to maintain structural integrity while generating aerodynamic forces. Methods: We analyzed the anatomical structure of bat wing skeletons in the context of scaling patterns relative to other mammals, material properties and the mechanical function of the wing bones during flight. Results: Compared with nonvolant mammals, the bones of the bat forelimb are elongated, even after correcting for shared phylogenetic history. Bats have consistently larger-diameter bones in the forelimb than do nonvolant mammals but significantly narrower hindlimb bones. Mineralization in the cortical bone of wings is lower than in the long bones of other adult mammals, with a proximodistal gradient of decreasing mineralization. The distal phalanges have only a small amount of mineralized tissue underlying the articular cartilage. Loads required to elicit a 10% length deflection in the wing bones of Glossophaga soricina varied approximately 50-fold along the wing and flexural stiffness nearly 200-fold. Commensurate with low mineralization and flexural stiffness, bat bones experience extraordinarily high bending strains during flight. Conclusion: Bat limb skeletons share features with other mammals and possess specialized characteristics, mostly related to the mechanical demands of flight.
Male and Female Breast Cancer – Differences in DNA Ploidy, p21 and p53 Expression Reinforce the Possibility of Distinct Pathways of Oncogenesis
Authors: André Saudade , Pinto António E. , Laranjeira Cátia , Quaresma Manuela , Soares Jorge
Published: December 2007

Aim: The purpose of this study was to compare the immunohistochemical profile of cell cycle inhibitors of G1/S phase transition (p21, p53 and pRb), Ki-67 proliferation marker and DNA ploidy in male (MBC) and female breast cancer (FBC). Material and Methods: One hundred patients (50 non-consecutive cases of FBC and an equal number of MBC) were selected according to homogeneous features regarding age, histological type, tumour grading, nodal status and absence of neoadjuvant therapy. The expression of p21, p53, pRb and Ki-67 was assessed by immunohistochemistry, and DNA ploidy was analysed by flow cytometry. Correlations between variables were evaluated using the χ2 test. Results: The incidence of DNA aneuploid, p21-positive and p53-negative tumours was significantly higher in MBC than in FBC; pRb and Ki-67 revealed no statistically significant differ- ences between the two entities. In MBC, high tumour grade correlated with aneuploidy, Ki-67 and pRb positivity; ploidy and p53 were also associated. In FBC, only ploidy and grade showed a strong correlation. Conclusion: The significant dissimilarities regarding DNA ploidy, p21 and p53 in these quite homogeneous groups of FBC and MBC point to different genomic instability and to differences in cell cycle proliferative control, reinforcing the view of somewhat distinct tumour oncogenesis.
Continuation and Maintenance Use of Antidepressants in Recurrent Depression
Authors: Bockting Claudi L.H. , ten Doesschate Mascha C. , Spijker Jan , Spinhoven Philip , Koeter Maarten W.J. , Schene Aart H.
Published: December 2007

Background: Maintenance antidepressant (AD) medication is the most commonly used preventive strategy in a highly recurrent disease, i.e. depression. Little is known about the discontinuation of maintenance AD use and the association with recurrence in daily clinical practice. The purpose was to examine the discontinuation rate of maintenance AD in daily clinical practice in recurrently depressed patients and the associated risk of recurrence. Methods: Prospectively AD maintenance medication and recurrence were examined in 172 euthymic patients with recurrent depression. AD user profiles before recurrence (nonusers, intermittent users, continuous users) were examined and related to recurrence over a 2-year follow-up period. Results: Less than half of the patients (42%) used AD continuously. Taking into account the minimal required adequate used dosage (≧20 mg fluoxetine equivalent), only 26% of the patients used AD as recommended by international guidelines. Despite continuous use of AD, 60.4% relapsed in 2 years. This relapse rate was comparable to the rate of the intermittent users (63.6%). In patients who stopped taking AD after remission and who received additional preventive CT, the recurrence rates were significantly lower than in non-AD-using patients treated with usual care (8 vs. 46%). Conclusions: The majority of recurrently depressed patients treated with AD discontinue maintenance AD therapy in daily primary and secondary clinical practice. AD seems to offer poor protection against relapse in this patient group. Patients who stopped using AD experienced less relapse, especially if they were treated with preventive CT. Alternative maintenance treatments (including preventive cognitive therapy after discontinuation of AD) should be studied in recurrently depressed patients with intermittent good remission, not only in secondary but also in primary care.
Mouse Models for Understanding the Growth Hormone Insulin-Like Growth Factor-I Axis
Authors: Rosen Clifford J.
Published: December 2007

Background: Mouse models that include spontaneous mutations, as well as those carrying allelic differences, have been extremely useful in clarifying the role of skeletal and circulating insulin-like growth factor I (IGF-I) in peak bone acquisition. The role of peroxisome proliferator-activated receptor gamma, a nuclear receptor and key differentiation factor for adipogenesis, has provided new insights into the relationship of marrow fat to skeletal mass. Conclusions: Mouse models continue to deepen our understanding of IGF-I signaling and the role of IGF-I in determining marrow stromal cell fate.
Insights from the Genetics of Severe Childhood Obesity
Authors: Farooqi Sadaf
Published: December 2007

Background: The identification and characterization of monogenic obesity syndromes have improved our understanding of the inherited component of severe obesity and have had undoubted medical benefits. This knowledge has also helped to dispel the notion that obesity represents an individual defect in behaviour with no biological basis. Conclusions: For individuals at highest risk for complications of severe obesity, such findings provide a starting point for providing more rational mechanism-based therapies, as has successfully been achieved for congenital leptin deficiency.
Endocrine Sequelae of Traumatic Brain Injury in Childhood
Authors: Acerini Carlo L. , Tasker Robert C.
Published: December 2007

Background: Anterior pituitary hormone dysfunction may be an important feature of long-term morbidity in survivors of traumatic brain injury (TBI). The hypothalamic-pituitary structures are vulnerable to damage following head injury. Therefore, pituitary dysfunction, which may be detected months or years after injury, is now well recognised as a long-term consequence of TBI in adults. In contrast, little is known about this potential complication in children and adolescents. This article reviews the available paediatric data, which show that hypopituitarism may occur after both mild and severe TBI, although there is little published data on its incidence or prevalence within this age group. A recent analysis of the KIGS (Pfizer International Growth Study database) highlights very few registered cases of TBI-related growth hormone deficiency, suggesting that this may be either an uncommon or an overlooked phenomenon. Prospective studies will be needed to determine the incidence, natural history and response to hormone replacement of post-TBI-induced hypopituitarism in children. Conclusions: Given the critical role of anterior pituitary hormones in the regulation of growth and pubertal and neurocognitive development in childhood, early detection of hormone abnormalities is vital. A multidisciplinary approach to follow-up and endocrine assessment is required for the long-term management and rehabilitation of children and adolescents who survive moderate to severe head injury.
Expanding the Genetic Spectrum of Noonan Syndrome
Authors: Noordam Kees
Published: December 2007

Background: The autosomal-dominant Noonan syndrome (MIM 163950) is characterized by short stature, typical facial dysmorphology and heart defects. Noonan syndrome is genetically heterogeneous. Over the last few years, germline mutations in four genes have been found in people with clinical signs of Noonan syndrome, accounting for approximately 65% of cases. All four genes encode proteins involved in the Ras–mitogen-activated protein kinase pathway and result in upregulation of this pathway. Recently, more data on final height after long-term growth hormone (GH) therapy has become available that shows its effectiveness in increasing final height for individuals with Noonan syndrome. Conclusions: The genetics underlying Noonan syndrome has been partially clarified over the last 5 years and further findings will undoubtedly be reported in the next few years. GH therapy has been used to treat patients with Noonan syndrome for approximately 15 years and is effective in improving adult height in affected children.
Thyroid Hormone Transporters
Authors: Visser Theo J.
Published: December 2007

Background: Cellular uptake and release of thyroid hormone are mediated by transporters. Among these, monocarboxylate transporter 8 (MCT8) shows particularly high activity towards the active thyroid hormone 3,3′,5-triiodothyronine (T3). MCT8 is expressed in different tissues, including the brain where it is predominantly localized in neurons. The MCT8 gene is located on the X chromosome. Conclusions: Mutations in MCT8 have been identified in boys with severe psychomotor retardation who also have very high serum T3 levels. Thyroid hormone is crucial for brain development, and mutations in MCT8 prevent the access of T3 to its main target cells. Thus, mutations in MCT8 represent a novel mechanism for the pathogenesis of thyroid hormone resistance.
Lessons from Sclerosing Bone Dysplasias
Authors: Van Hul Wim
Published: December 2007

Background: Bone mineral density (BMD) is influenced by both genetic and environmental factors. The role of genetic factors in bone homeostasis is clearly illustrated by a group of genetic conditions associated with abnormal BMD. These conditions are often monogenic, caused by mutations in one gene. Conclusions: Major breakthroughs in understanding the molecular pathogenesis of these conditions will allow molecular evaluation of patients and provide useful tools for genetic counseling. Genetic studies also provide new insights into bone metabolism, identifying potential promising targets for therapeutic agents for osteoporosis and osteoporotic disorders.
Headache, Idiopathic Intracranial Hypertension and Slipped Capital Femoral Epiphysis during Growth Hormone Treatment: A Safety Update from the KIGS Database
Authors: Darendeliler Feyza , Karagiannis Georgios , Wilton Patrick
Published: December 2007

Background: Several uncommon adverse effects may be related to growth hormone (GH) treatment. Three potential side effects, headache, idiopathic intracranial hypertension (IIH) and slipped capital femoral epiphysis (SCFE), will be discussed. Data from 57,968 children in the KIGS (Pfizer International Growth Study database) were analyzed to determine the effects of recombinant human GH (Genotropin®) on these side effects. The diagnostic groups were idiopathic GH deficiency (IGHD) (n = 27,690), congenital GHD (CGHD) (n = 2,547), craniopharyngioma (n = 1,155), cranial tumours (n = 2,203), Turner syndrome (TS) (n = 6,092), idiopathic short stature (ISS) (n = 5,286), small for gestational age (SGA) (n = 2,973), chronic renal insufficiency (CRI) (n = 1,753) and Prader-Willi syndrome (PWS) (n = 1,368). Results: Total incidence (per 100,000 treatment years) of headache was 793.5 (n = 569). The incidence was significantly higher in the groups of patients with craniopharyngiomas, CGHD and cranial tumours than in the other diagnostic groups (p < 0.05 for all). IIH occurred in 41 children resulting in a total incidence (per 100,000 treatment years) of 27.7. The incidence (per 100,000 treatment years) was significantly lower in patients with IGHD (12.2) than in those with TS (56.4) (p = 0.0004), CGHD (54.5) (p = 0.0064), PWS (68.3) (p = 0.0263) and CRI (147.8) (p < 0.001). No cases of IIH were reported in the ISS group of patients. The median duration from onset of GH therapy to IIH ranged from 0.01 to 1.3 years in various diagnostic groups. SCFE was observed in a total of 52 children resulting in a total incidence (per 100,000 treatment years) of 73.4. The incidence (per 100,000 treatment years) was significantly lower in patients with IGHD (18.3) and in those children with ISS (14.5) than in the TS (84.5), cranial tumours (86.1) and craniopharyngioma groups (120.5) (p < 0.05 for all). No cases of SCFE were reported in the SGA and PWS groups. The median duration from onset of GH therapy to SCFE ranged from 0.4 to 2.5 years. Conclusions: The incidences of IIH and SCFE in this analysis are lower than the values reported in previous KIGS analyses and comparable to other databases. Patients with TS, organic GHD, PWS and CRI seem to be more prone to these side effects.
Future Directions: Growth Prediction Models
Authors: Geffner Mitchell E. , Dunger David B.
Published: December 2007

Background: One strategy for optimizing growth hormone (GH) treatment is to develop mathematical models based on clinical data from the large numbers of subjects in the KIGS (Pfizer International Growth Study Database) and to compare the observed versus predicted growth responses in subjects with short stature secondary to idiopathic GH deficiency (GHD), Turner syndrome, small birth size and idiopathic causes of short stature. Mathematical Models: Variables employed in derived regression equations include those related to birth status, genetic potential, current clinical status, laboratory data and GH treatment schedule. These models can provide an accurate estimate of potential growth on GH therapy and the tools to optimize and individualize GH therapy to obtain maximum height with the least risk and the lowest cost. Current prediction models explain around 58% of GH responsiveness in subjects with GHD, 46% in subjects with Turner syndrome and 52% in those born small for gestational age. Future Considerations: The predictive value of these models could be improved by the inclusion of extended anthropometric variables and biological parameters such as insulin-like growth factor I levels. However, recent reports that common polymorphisms of theGH receptor (GHR) gene may be associated with variations in response to GH suggest that, in the future, molecular genetics may provide an additional tool for refining growth prediction models. This possibility is being explored in a pilot study examining the effects of candidate genes in a targeted KIGS population to determine whether the GHR geneor other gene variants contribute to growth response over the first year of GH treatment.
Concepts in the Diagnosis of Adult Growth Hormone Deficiency
Authors: Biller Beverly M.K.
Published: December 2007

Background: To make a diagnosis of growth hormone deficiency (GHD), individuals with normal GH levels must be distinguished from those who are deficient. This requires an understanding of how GH secretion and other related factors differs between these two groups. The presence of a normal insulin-like growth factor I (IGF-I) level does not necessarily preclude a diagnosis of GHD, whereas a low IGF-I level in a subject with three or four other hormone deficiencies and no conditions that would otherwise lower IGF-I might be sufficient to make the diagnosis. Provocative testing is a clinically relevant method of testing, but not all tests in use have comparable specificity and sensitivity. Conclusions: Insulin-induced hypoglycemia is the recommended test to diagnose GHD, but the arginine-GH-releasing hormone test achieves comparable separation between normal and hypopituitary subjects in most groups. Future studies using large surveillance databases may further expand our understanding of concepts underlying GHD and its diagnosis.
Congenital Adrenal Hyperplasia: A Lifelong Disorder
Authors: Hughes Ieuan A.
Published: December 2007

Background: Congenital adrenal hyperplasia (CAH), the most common cause of ambiguous genitalia of the newborn, requires rapid assessment by a multidisciplinary team including a neonatologist, paediatric endocrinologist, paediatric urologist and geneticist. There is also a role for the clinical psychologist with psychosexual counselling experience as families cope with disorders of sex development. This brief review summarises the continuum of disorders that are manifested in patients with CAH according to age and sex, with emphasis on the lifetime nature of the issues that accompany this disorder and on the long-lasting ramifications of pediatric management decisions for both males and females. Conclusions: There are many management aspects of caring for patients with CAH that clearly fall into the purview of paediatricians or adult-care physicians. There are also areas where responsibilities overlap and require several professionals providing coordinated care.
Multiple Endocrine Neoplasia Type 2: 2007 Update
Authors: Raue Friedhelm , Frank-Raue Karin
Published: December 2007

Background: Multiple endocrine neoplasia type 2 (MEN-2) is an autosomal dominant tumour syndrome caused by germline-activating mutations of the RET proto-oncogene. It is clinically characterised by the presence of medullary thyroid carcinoma (MTC), bilateral pheochromocytoma and primary hyperparathyroidism (MEN-2A) within a single patient. Three distinct clinical forms have been described depending on the phenotype: (1) classic MEN-2A, (2) MEN-2B, an association of MTC, pheochromocytoma and mucosal neuroma and (3) familial MTC (FMTC), which is associated with a low incidence of other endocrinopathies. Each variant of MEN-2 results from a different RET gene mutation, with a good genotype-phenotype correlation. Detection and Treatment: Genetic testing detects nearly 100% of mutation carriers and is considered the standard of care for all first-degree relatives of patients with newly diagnosed MTC. Recommendations on the timing of prophylactic thyroidectomy and extent of surgery are based on a three risk-level classification using the genotype-phenotype correlations. Conclusions: MEN-2 provides a unique model for early prevention and cure of cancer and for stratified roles of mutation-based diagnosis of carriers.
Endocrine Surgical Aspects of Multiple Endocrine Neoplasia Syndromes in Children
Authors: Harrison Barney
Published: December 2007

Background: All patients diagnosed with medullary thyroid carcinoma (MTC) should undergo RET mutation analysis to exclude familial disease – multiple endocrine neoplasia (MEN)-2A and -2B and familial medullary thyroid carcinoma (FMTC). In young patients at risk of genetically determined MTC, the key to a good outcome is an appropriate first operation, and this will depend upon the codon mutation, patient age, calcitonin level and disease extent at presentation. When MTC has already developed, a therapeutic intervention is required. Conclusions: The thyroid, pituitary, adrenal, parathyroid and pancreatic components of MEN-1 and -2 require close collaboration of a specialist and experienced multidisciplinary team.
Update on the Management of Congenital Hypothyroidism
Authors: Grüters Annette , Krude Heiko
Published: December 2007

Background: Congenital hypothyroidism (CH) is the most frequent congenital endocrine disorder. The diagnosis in industrialized countries is usually made with population-based newborn screening that measures thyroid-stimulating hormone (TSH) or TSH and total thyroxine (T4) in dried blood spots in the first 3 days of life. In newborns with a screening result suspicious for hypothyroidism, the diagnosis of primary CH is confirmed when serum TSH levels are above and T4 (free T4) levels are below the age-related reference ranges. Hypothalamic-pituitary hypothyroidism is more difficult to diagnose. Most infants with this diagnosis are missed in screening programs unless T4 (free T4)/TSH or TSH/T4/thyroxine binding globulin is simultaneously measured. If hypothyroidism is confirmed by laboratory analysis, imaging studies should be performed immediately; however, it is not acceptable to delay hormone replacement therapy if imaging studies are not readily available. Conclusions: The goal of treatment of CH is to avoid disturbed mental development, and initial treatment can be adjusted to physiological conditions. To match the higher thyroid hormone concentrations in the first weeks of life, substitution with l-thyroxine should aim to achieve serum T4/free T4 levels in the upper half of the normal age-related reference range. Some newborns and infants will have persistently high TSH levels despite normalized T4/free T4 serum concentrations.
Improving Growth in Children with Inflammatory Bowel Disease
Authors: Ahmed S. Faisal , Wong Jarod S.C. , McGrogan Paraic
Published: December 2007

Background: Growth in children with inflammatory bowel disease (IBD) is affected through a number of mechanisms; controlling disease activity and supporting poor nutritional status are paramount in these patients. Further understanding of the basic mechanisms by which cytokines influence growth will facilitate the development of therapeutic modalities to improve growth. Conclusions: Clinical management that addresses growth and puberty in children with IBD should be a partnership between paediatric gastroenterologists and endocrinologists. Well-designed studies of growth-promoting hormonal treatment may answer questions regarding the efficacy and safety of treating growth retardation in the subgroup of patients who continue to fail to grow despite optimal management of their IBD.
Management of Growth Retardation in Juvenile Idiopathic Arthritis
Authors: Simon Dominique
Published: December 2007

Background: Inflammation and glucocorticoid therapy are major factors in the growth retardation seen in children with severe forms of juvenile idiopathic arthritis (JIA). It has been recently shown that tumor necrosis factor (TNF)-α antagonist therapy can improve growth velocity in JIA patients; however, the recombinant human soluble TNF-α receptor fusion protein etanercept has had limited efficacy in systemic forms of JIA. For several years, growth hormone (GH) has been used to treat growth retardation in patients with JIA receiving glucocorticoids. GH treatment can normalize growth velocity and prevent the severe loss of height; however, catch-up growth markedly varies with the severity of the inflammatory state and the steroid doses used during GH treatment. Recently, early institution of GH treatment has been shown to maintain normal growth in children with JIA. Conclusions: These promising results show the need for careful monitoring of growth in children with JIA, the utility of GH therapy before the onset of severe growth delay and the potential for preservation of long-term growth during disease progression.
Aryl Hydrocarbon Receptor-Interacting Protein and Acromegaly
Authors: Aaltonen Lauri A.
Published: December 2007

Background: Recently, researchers at the Oulu University Hospital and the University of Helsinki identified a large pedigree segregating prolactinomas and somatotropinomas. Results suggest that this family from Northern Finland has a possible low penetrance of hereditary predisposition to development of pituitary adenoma, and in particular growth hormone-secreting tumors. We applied cancer genetics tools such as genomic and expression arrays to identify the gene responsible for the tumors identified in this kindred and found that the same ancestral founding mutation caused the disease. Review of population-based data showed that approximately 45 individuals were diagnosed with acromegaly in this area of Finland within a limited time frame. Of those individuals, 16% were positive for a mutation of the aryl hydrocarbon receptor-interacting protein (AIP) mutation. We proposed using the term pituitary adenoma predisposition (PAP) to describe a person with an AIP germline mutation. Tumor immunohistochemistry testing can be used for subjects with a reasonable suspicion of PAP to determine whether the tumor is negative for the AIP protein. If so, the subject can be referred for genetic counseling and then can decide whether to undergo genetic testing. Conclusions: Further study is needed to further define the PAP syndrome, delineate its phenotype and determine whether there is some component tumor associated with it. Functional work on AIP should shed new light on the mechanisms of pituitary tumorigenesis.
Targeting Pituitary Tumors
Authors: Heaney Anthony P.
Published: December 2007

Background: Pituitary tumors are common and usually grow insidiously over many years. Rarely fatal, treatment still requires multiple cytoreductive surgeries and/or radiation therapy with its attendant side effects. As a disease process of regulatory pathways, pituitary tumors offer numerous potential therapeutic targets, and many, such as the membranal dopamine2 and somatostatin receptors, have been successfully exploited for many years. Nuclear receptors, such as the estrogen receptor, peroxisome proliferator-activating receptor and retinoic acid receptor, are abundantly expressed in pituitary tumors, and a variety of increasingly potent and specific ligands are emerging. Subcellular therapies aimed at the pituitary tumor transforming gene may also have some utility in pituitary tumor management, though obstacles to targeting nuclear proteins using gene therapy still exist. Other novel agents such as doxazosin, an α-adrenoceptor blocker that appears to inhibit nuclear signaling mediated by nuclear factor kappa-B (NFĸB), and epidermal growth factor receptor may also represent new and safe medical therapies for these benign but problematic tumors. Conclusions: Increased understanding regarding the etiopathogenesis of pituitary tumors has identified new proteins and pathways that may lead to novel therapies. Empiric exploration of novel targeted therapies developed for other tumor types, guided by pharmacogenomic profiling studies, will likely reveal the utility of many of these novel targeted agents in the treatment of pituitary tumors.
Adrenal Incidentalomas: Presentation and Clinical Work-Up
Authors: Beuschlein Felix
Published: December 2007

Background:Through the widespread use of imaging techniques with great sensitivity, adrenal tumours are often diagnosed as an incidental finding. The majority of these adrenal lesions are benign and without evidence of endocrine activity or malignancy. However, in addition to the classic forms of overt adrenal hypersecretion, it has become evident in recent years that even modest adrenal hormonal autonomy, as exhibited in clinically silent phaeochromocytoma, normokalaemic primary aldosteronism and subclinical Cushing syndrome, is associated with significant morbidity. Thus, hormone hypersecretion and growth kinetics must be ruled out for each patient using specific tests to avoid associated morbidity. Conclusions:Detection and differential diagnosis of subtle changes in adrenal hormone secretion can pose a diagnostic challenge to the clinician, and accurate diagnosis is dependent on use of tests with reliable sensitivity and specificity.
Thyroid Incidentalomas
Authors: Pinchera Aldo
Published: December 2007

Background: The prevalence of thyroid nodules in the general population varies according to the method of detection in use. In large population studies, about 5% of subjects have palpable thyroid nodules, while autopsy studies reveal a 49–57% prevalence of thyroid nodules that were asymptomatic during life, and thyroid ultrasonography (US) shows a 13–50% prevalence in the general population. The increased sensitivity of many imaging modalities has led, in turn, to increased detection of subclinical thyroid nodules and of small, nonpalpable incidentalomas, and a diagnostic approach to patients with these nodules is briefly summarized. Conclusions: Despite the high prevalence of thyroid nodules discovered by US, clinically relevant thyroid malignancy remains rare and can be managed conservatively in most cases.
Pediatric Intracranial Meningiomas – Do They Differ from Their Counterparts in Adults?
Authors: Arivazhagan A. , Devi B. Indira , Kolluri Sastry V.R. , Abraham R.G. , Sampath S. , Chandramouli B.A.
Published: December 2007

Aim: Meningiomas are very rare in children comprising only 0.44.1% of pediatric age tumors and only 1.5–1.8% of all intracranial neoplasms. We analyzed the clinical, pathological and management profile of these rare tumors and elucidated their differences from meningiomas in adults. Methods: From 1990 to 2005, 33 patients belonging to the pediatric age group with intracranial meningiomas were treated in NIMHANS. Results: There were 19 male and 14 female children. The duration of symptoms ranged from 1 to 60 months. The study had a mean follow-up of 23.4 months. The commonest presenting symptoms were headache (90.9%) and visual disturbances (51.5%). Three patients had associated neurofibromatosis. Calcification was noticed in 22% of the tumors. Intraventricular meningiomas were the commonest (24.2%). Gross total or near total resection was possible in 22 out of 33 patients. Nine patients had reversible postoperative motor deficits. Fibrous meningioma was the commonest histological subtype (24.2%). Five patients had atypical or anaplastic subtypes. Adjuvant radiotherapy was administered in 4 patients. Six patients had recurrences and underwent surgery. Ten patients required either staged procedures or multiple surgeries for the recurrence/residual tumors. Conclusion: Pediatric meningiomas are rare tumors and differ from those in adults by their male predominance, atypical locations, higher rates of malignant subtypes, recurrence and association with neurofibromatosis. Surgical management is challenging because of atypical location.
Unusual Ventriculoperitoneal Shunt Extrusion: Experience with 5 Cases and Review of the Literature
Authors: Kanojia Ravi , Sinha Shandip K. , Rawat Jiledar , Wakhlu Ashish , Kureel Shivnarain , Tandon Rajkumar
Published: December 2007

Distal migration of ventriculoperitoneal shunt is rare. We present this unusual complication in 5 patients. The lower end of the shunt was extruded from right lumbar region, cervical area, umbilicus and rectum. The cause of such extrusion is not known. The patients were managed by shunt removal followed by shunt replacement on the opposite side.
Transcortical Approach to a Huge Pineal Mature Teratoma
Authors: Berhouma Moncef , Jemel Hafedh , Ksira Iadh , Khaldi Moncef
Published: December 2007

Intracranial teratomas are rare germ cell neoplasms occurring more often during childhood. We report the case of a huge mature teratoma of the pineal region in a 10-year-old patient that was not correctly diagnosed preoperatively by stereotactic biopsy. The tumor was revealed by intracranial hypertension and a Parinaud syndrome. The tumor markers were within normal levels in the serum. A left transcortical parietal approach was used to completely resect the tumor. No adjuvant treatment was given. A complete neurological recovery was observed after the surgical procedure. Follow-up at 2 years did not show any recurrence. Pineal mature teratomas have a good prognosis, in contrast to their immature or mixed counterparts. A rigorous histological examination of the tumor samples is mandatory, in order to not omit a mixed contingent within the tumor. The treatment is exclusively surgical.
Hydrothorax: Transdiaphragmatic Migration of a Ventriculoperitoneal Shunt Catheter
Authors: Ergün Rüçhan , Ökten Ali İhsan , Gezercan Yurdal
Published: December 2007

Symptomatic hydrothorax following ventriculoperitoneal shunt insertion is a very rare complication. The patient was a 5-month-old child known to have had shunted congenital hydrocephalus two months before. He presented to the emergency room in respiratory distress. Chest X-ray and computerized tomography images confirmed left hydrothorax and showed transdiaphragmatic migration of the tip of the peritoneal catheter to the thoracic cavity. After the catheter had been shortened and replaced to the peritoneal cavity, the patient’s symptoms abated.
Cerebrospinal Fluid Shunting in Children on Renal Dialysis
Authors: Manning Thomas C. , Avellino Anthony M. , Symons Jordan , Ojemann Jeffery , Ellenbogen Richard G.
Published: December 2007

The concurrent need for both cerebrospinal fluid shunting for hydrocephalus and dialysis for end-stage renal disease is rare. No large case series are found in the literature. Because dialysis involves frequent access to either the peritoneal cavity or the venous system, concern over potential cerebrospinal shunt infection represents a point of concern. We present 2 cases in which patients underwent both dialysis and cerebrospinal fluid shunting. In one case, a child underwent ventriculoperitoneal shunting, while in the second case ventriculoatrial shunting was performed as the initial procedure. Management strategies and potential complications are discussed.
Management of Hepatocellular Carcinoma in Japan: Consensus-Based Clinical Practice Manual Proposed by the Japan Society of Hepatology
Authors: Kudo Masatoshi , Okanoue Takeshi
Published: December 2007

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death not only in Japan but worldwide. Clinical Practice Guidelines for HCC were published in 2001 by the European Society of Study of the Liver (EASL) and in 2005 by the American Association for the Study of Liver Disease (AASLD). However, these guidelines have proven to be somewhat unsuitable for Japanese patients. In 2005, supported by the Japanese Ministry of Health, Labor and Welfare, Evidence-Based Clinical Practice Guidelines for HCC were compiled. Based on ‘evidence-based’ guidelines and the consensus of an expert panel on HCC, the Japan Society of Hepatology (JSH) published the Consensus-Based Clinical Practice Manual in 2007. In this article, the content of this manual, especially issues on surveillance, diagnosis, staging, and treatment, is summarized.
Natural Course of Small Nodular Lesions with Intranodular Preserved Portal Supply in Cirrhotic Liver
Authors: Fukunaga Toyokazu , Kudo Masatoshi , Tochio Hitoshi , Okabe Yoshihiro , Orino Akio
Published: December 2007

Background and Aim: Due to recent advances in imaging technology, small nodules or lesions in cirrhotic liver are now seen easily. Intranodular blood supply is useful in characterizing these nodules. However, nodules with preserved portal blood supply may be malignant or benign, and it is unknown how often these nodules develop into overt hepatocellular carcinoma (HCC). This study was performed to clarify the rate of malignant transformation in such lesions with preserved portal perfusion in cirrhotic liver. Methods: From 1995 to 1997, in 98 patients, we performed CT during arterial portography and ultrasound angiography with intra-arterial CO2 injection for 113 nodules <3 cm in diameter to determine the intranodular blood supply. Of these, 48 nodules in 36 patients were diagnosed as ‘benign nature nodules’ on the basis of the blood supply of the nodules, which included arterial hypovascularity with preserved portal supply. Percutaneous biopsy of the nodule was undertaken for all nodules for histopathologic diagnosis. Thirty-two nodules in 22 patients that were not diagnosed as early HCC were followed-up clinically without any treatment to clarify the natural course of the nodules. Results: Twelve nodules in 14 patients did not increase in size and no new nodules appeared in any part of the liver. Ten nodules in 7 patients did not increase in size or arterial vascularity but typical overt HCC appeared in other areas of the liver. Only two nodules in 2 patients increased in size and developed into hypervascular overt HCC during the 15- and 34-month observation periods, respectively. Conclusion: Nodules with preserved portal perfusion in cirrhotic liver have a low risk of malignant transformation compared with the surrounding liver parenchyma.
Superiority of CT Arterioportal Angiography to Contrast-Enhanced CT and MRI in the Diagnosis of Hepatocellular Carcinoma in Nodules Smaller than 2 cm
Authors: Kim Soo Ryang , Ando Kenji , Mita Keiji , Fuki Shuichi , Ikawa Hirotsugu , Kanbara Yoshihiro , Imoto Susumu , Matsuoka Toshiyuki , Hayashi Yoshitake , Kudo Masatoshi
Published: December 2007

To evaluate the effectiveness of computed tomography (CT) arterioportal angiography in the diagnosis of hepatocellular carcinoma (HCC) in nodules smaller than 2 cm, we compared the findings of CT during arteriography (CTA) and CT during arterial portography (CTAP) with those of enhanced CT and enhanced magnetic resonance imaging (MRI). Sixty-eight nodules smaller than 2 cm in 53 patients with liver cirrhosis were classified into three groups of CTA and CTAP: (group 1) hyperattenuation on CTA, and hypoattenuation on CTAP (56 nodules, 41 patients); (group 2) hypoattenuation on CTA, and hypoattenuation on CTAP (10 nodules, 10 patients); (group 3) hypoattenuation on CTA, and hyperattenuation on CTAP (2 nodules, 2 patients). Histologically, 96% (54/56), 80% (8/10), and 100% (2/2) of the nodules in groups 1, 2 and 3, respectively, were diagnosed as HCC. In group 1, enhanced CT or enhanced MRI confirmed hypervascularity in only 77% (30/39) and venous washout in 21% (8/39). In groups 2 and 3, enhanced CT or enhanced MRI on 7 and 2 nodules, respectively, revealed no hypervascularity (0%). The results suggested that CT arterioportal angiography is superior to enhanced CT and MRI in nodules smaller than 2 cm for diagnosing HCC (p < 0.01 group 1, p < 0.01 group 2).
Treatment of Hepatocellular Carcinoma Using Internally Cooled Electrodes
Authors: Cua Ian Homer Y. , Lin Chen-Chun , Lin Chun-Jung , Chen Wei-Ting , Hsu Chao-Wei , Chen Yi-Cheng , Wong Stephen N. , Lin Shi-Ming
Published: December 2007

Objectives: To compare the effectiveness of modified automated and manual pulsed radiofrequency (RF) algorithms using internally cooled electrodes for hepatocellular carcinoma (HCC). Methods: Seventy-seven treatment-naive cirrhotic patients with 102 HCC (≤4 cm) underwent 109 sessions of ultrasound-guided percutaneous RF ablation using a 17-gauge, 20-cm-long, single internally cooled electrode. Patients were assigned alternatively: 40 patients to the modified automated algorithm group and 37 patients to the manual algorithm group. The mean tumor diameters were 2.34 ± 0.9 and 2.25 ± 0.7 cm in the automated and manual groups, respectively (p = 0.56). Primary technique effectiveness and local tumor progression were compared between the two groups. Results: More overlapping ablations (n = 112) were required in the manual than in the automated group (n = 82) to achieve similar primary technique effectiveness rates of 96.1 and 94.1%, respectively. After a mean follow-up period of 26.7 ± 1.1 months, the local tumor progression rates at 12 and 18 months were 4 and 20% in the manual group and 12 and 24% in the modified automated group (p = 0.3). Only tumors >3 cm were independently associated with local tumor progression (odds ratio 1.25; 95% CI 1.06–2.34, p = 0.03). Conclusions: The manual algorithm requires more overlapping ablations and treatment sessions in order to achieve similar primary technique effectiveness and local tumor progression rates compared with the modified automated algorithm.
What Is the Best Time to Evaluate Treatment Response after Radiofrequency Ablation of Hepatocellular Carcinoma Using Contrast-Enhanced Sonography?
Authors: Zhou Pei , Kudo Masatoshi , Minami Yasunori , Chung Hobyung , Inoue Tatsuo , Fukunaga Toyokazu , Maekawa Kiyoshi
Published: December 2007

Purpose: To observe the visibility and changes in the echogenicity of ablated tumor and ablated nontumor areas after radiofrequency ablation (RFA) over time using gray-scale sonography, and, consequently, to decide on the best timing for contrast-enhanced sonography to evaluate the response of hepatocellular carcinoma to RFA. Materials and Methods: Thirty-eight patients with 48 hepatocellular carcinoma nodules underwent RFA. Consecutive gray-scale sonographic observations were made 10 min before RFA and at five points within 4 days after RFA. Two hepatologists blindly reviewed the sonographic images to assess the identifiability of the boundary of the ablated nodules and to semiquantitatively score the echogenicity of the ablated tumor and ablated nontumor regions in 15 hypoechoic nodules with detectable boundaries within 4 days after RFA. Results: The detection rates of the boundaries of ablated tumors were 56.5, 65.2, 54.3, 43.5, and 39.1% at 3–6 h and 15–22 h and on the 3rd, 4th, and 5th days after RFA. There was a significant difference between the detection rate for ablated tumors at 15–22 h and that on the 3rd and 4th days. The difference in echogenicity between ablated tumor and ablated nontumor tissue reached a maximum at 15–22 h after RFA. Conclusion: Ablated tumor can be clearly identified within the ablated area in 65.2% of cases using gray-scale sonography at 15–22 h after RFA. The day following RFA is most appropriate and practical for the performance of contrast-enhanced sonography to evaluate the therapeutic response, including a safety margin.
Initial Treatment Response Is Essential to Improve Survival in Patients with Hepatocellular Carcinoma Who Underwent Curative Radiofrequency Ablation Therapy
Authors: Takahashi Shunsuke , Kudo Masatoshi , Chung Hobyung , Inoue Tatsuo , Ishikawa Emi , Kitai Satoshi , Tatsumi Chie , Ueda Taisuke , Minami Yasunori , Ueshima Kazuomi , Haji Seiji
Published: December 2007

Objective: This study was undertaken to assess the outcome of potentially curative radiofrequency ablation (RFA) therapy for early-stage hepatocellular carcinoma (HCC) in patients with Child-Pugh stage A cirrhosis. Methods: This study retrospectively evaluated clinical outcomes in a cohort of 171 Child-Pugh stage A cirrhotic patients who received RFA for naïve HCC within the Milan criteria. The median follow-up period was 36.7 months. Results: Cumulative survival rates estimated by the Kaplan-Meier method for all patients were 98.8, 91.1 and 76.8% at 1, 3 and 5 years, respectively. Cumulative probabilities of local tumor recurrence at 1, 2 and 3 years were 9.0, 14.1 and 17.7%, respectively. Cumulative survival rates in patients without local tumor recurrence were 96.6, 94.6 and 84.4% at 1, 3 and 5 years, respectively, compared with patients with local tumor recurrence (96.6, 74.8 and 42.1% at 1, 3 and 5 years, respectively; p = 0.0002). Cox regression analysis showed that low serum albumin (p = 0.009, RR 3.04, CI 1.32–6.98), high range of PIVKA-II (prothrombin induced by vitamin K absence or agonist II) (p = 0.025, RR 2.57, CI 1.13–5.89), with multiple (less than 3) nodules (p = 0.021, RR 2.61, CI 1.15–5.91), and with local tumor recurrence (p = 0.004, RR 3.62, CI 1.51–8.69) were significant risk factors for death. Conclusion: Initial complete response of curative RFA therapy in patients with Child-Pugh stage A cirrhosis and early-stage HCC is associated with improved survival. Therefore, clinicians should aim to achieve complete ablation of all detectable HCC nodules with adequate safety margins.