ABSTRACT
BACKGROUND: This study characterises molecular effect of bevacizumab, and explores the relation of molecular and genetic markers with response to bevacizumab combined with chemoradiotherapy (CRT). METHODS: From a subset of 59 patients of 84 rectal cancer patients included in a phase II study combining bevacizumab with CRT, tumour and blood samples were collected before and during treatment, offering the possibility to evaluate changes induced by one dose of bevacizumab. We performed cDNA microarrays, stains for CD31/CD34 combined with α-SMA and CA-IX, as well as enzyme-linked immunosorbent assay (ELISA) for circulating angiogenic proteins. Markers were related with the pathological response of patients. RESULTS: One dose of bevacizumab changed the expression of 14 genes and led to a significant decrease in microvessel density and in the proportion of pericyte-covered blood vessels, and a small but nonsignificant increase in hypoxia. Alterations in angiogenic processes after bevacizumab delivery were only detected in responding tumours. Lower PDGFA expression and PDGF-BB levels, less pericyte-covered blood vessels and higher CA-IX expression were found after bevacizumab treatment only in patients with pathological complete response. CONCLUSIONS: We could not support the 'normalization hypothesis' and suggest a role for PDGFA, PDGF-BB, CA-IX and α-SMA. Validation in larger patient groups is needed.
Subject(s)
Angiogenesis Inhibitors/administration & dosage , Antibodies, Monoclonal, Humanized/administration & dosage , Biomarkers, Tumor/blood , Gene Expression Regulation, Neoplastic/drug effects , Rectal Neoplasms/therapy , Adult , Aged , Angiogenesis Inhibitors/pharmacology , Antibodies, Monoclonal, Humanized/pharmacology , Bevacizumab , Biomarkers, Tumor/genetics , Chemoradiotherapy , Clinical Trials, Phase II as Topic , Gene Expression Profiling , Humans , Male , Middle Aged , Oligonucleotide Array Sequence Analysis , Rectal Neoplasms/blood , Rectal Neoplasms/pathology , Translational Research, Biomedical , Treatment OutcomeABSTRACT
AIM: Recently, 18F-labeled 2-(5-fluoropentyl)-2-methylmalonic acid or ML10 has been proposed as a promising PET tracer for imaging of apoptosis. In this study we compared 18F-ML10, the 123I labeled 5-iodo derivative (123I-ML10) and a 68Ga-labeled Annexin A5 (AnxA5) and evaluated them as apoptosis tracers in several distinct models. METHODS: In vivo stability and biodistribution were studied in healthy mice. Apoptosis imaging was evaluated in anti-Fas treated mice and mice with muscular apoptosis. Furthermore, 18F-ML10 and 68Ga-Cys2-AnxA5 were evaluated in a rat model with reperfused liver infarct and a rat model with cerebral infarct as well as in Daudi tumor bearing mice, before and after treatment with cyclophosphamide and/or radiotherapy. RESULTS: 18F-ML10 and 68Ga-Cys2-AnxA5 were both stable, while 123I-ML10 metabolized very quickly in vivo. All tracers showed a 3-4 times higher uptake in apoptotic muscular tissue in comparison to that in healthy muscular tissue. Animals with anti-Fas induced hepatic apoptosis showed an increased liver uptake which was most pronounced for 18F-ML10. The uptake of both 18F-ML10 and 68Ga-Cys2-AnxA5 increased in the apoptotic region surrounding the cerebral infarction and the reperfused liver infarction. Tumor uptake of 68Ga-Cys2-AnxA5, but not of 18F-ML10, was statistically significantly higher after therapy as measured with PET/MRI. CONCLUSION: All radiotracers were able to detect apoptosis in vitro and in vivo in each of the studied animal models of apoptosis. 68Ga-Cys2-AnxA5, but not 18F-ML10, allowed to visualize the effect of tumor therapy in a statistically significant way.
Subject(s)
Annexin A5 , Methylmalonic Acid/analogs & derivatives , Neoplasms, Experimental/diagnostic imaging , Neoplasms, Experimental/radiotherapy , Positron-Emission Tomography/methods , Animals , Apoptosis , Cell Line, Tumor , Fluorine Radioisotopes , Gallium Radioisotopes , Iodine Radioisotopes , Isotope Labeling , Male , Mice , Neoplasms, Experimental/pathology , Radiopharmaceuticals , Rats , Reproducibility of Results , Sensitivity and Specificity , Treatment OutcomeABSTRACT
The authors present two patients with Delleman syndrome and one in with possible ECCL. Two boys with Delleman syndrome showed characteristic dysmorphic features with cerebral, ocular and skin malformations. The ocular anomalies consisted of eyelid coloboma, microphthalmia, iris coloboma and epibulbar lypodermoids. A third boy with possible ECCL syndrome had limbal lypodermoids, ectopia pupillae and aberrant iris tissue in the right eye. He showed an ipsilateral focal dermal hypoplastic defect within an area of alopecia of the scalp.
Subject(s)
Abnormalities, Multiple/diagnosis , Eye Abnormalities/diagnosis , Face/abnormalities , Brain/abnormalities , Child, Preschool , Humans , Infant, Newborn , Male , Scalp/abnormalities , SyndromeABSTRACT
Preschoolers (27 boys, mean age = 4.7 yr.; 24 girls, mean age = 4.6 yr.) were assessed for field dependence-independence (Preschool Embedded Figures Test), sex-role stereotyping (Sex-role Learning Inventory), and receptive verbal intelligence (Peabody Picture Vocabulary Test--Revised). Relative to the girls, the boys were significantly less field-independent and significantly more sex-role stereotyped. After age and Peabody IQs were partialled out by multiple regression, same-sex typing in boys and cross-sex typing in girls were significant predictors of field independence. The regression analysis also suggested that, by 5.3 yr. of age, the boys as a group surpassed the girls on field independence. Limitations of the present research and educational implications of the over-all findings are discussed.
Subject(s)
Field Dependence-Independence , Gender Identity , Personality Development , Stereotyping , Age Factors , Child, Preschool , Female , Humans , Male , Personality Tests , Problem SolvingABSTRACT
The clinical, biochemical and electrophysiologic features of two patients with abetalipoproteinemia, a 17 year old boy and his sister of 14, are reported. They are the second and third reports of this disease in Belgium. Diagnosis was made by the Apo-B deficiency in their serum and the normal levels in their parents'. According to other investigators we revealed in both cases deficiency of other apoproteins, indicating, that the metabolic defect affects all classes of plasma lipoproteins. EMG findings showed axonal neuropathy. Somatosensory evoked potentials demonstrated dorsal column dysfunction. Findings were consistent with the known neuropathology of abetalipoproteinemia and of vitamin E deficiency syndromes. The therapeutic role of vitamin E is discussed.
Subject(s)
Abetalipoproteinemia/physiopathology , Abetalipoproteinemia/drug therapy , Abetalipoproteinemia/pathology , Adolescent , Blood Chemical Analysis , Electrophysiology , Evoked Potentials, Somatosensory , Female , Humans , Intestinal Mucosa/pathology , Male , Nervous System Diseases/physiopathology , Vitamin E/therapeutic useABSTRACT
Neuropathological data from the autopsy of a 5 1/2 year-old female patient with the Wiedemann-Rautenstrauch or neonatal progeroid syndrome are reported. Extensive demyelination is found in the central nervous system with occasionally a tigroid pattern and with large amounts of neutral fats and intermediate debris of myelin breakdown in macrophages. These lesions are characteristic of pure sudanophilic leucodystrophy. Features differentiating the findings from those in Pelizaeus-Merzbacher disease and in other disorders associated with sudanophilic leucodystrophy with various special characteristics are presented and discussed.
Subject(s)
Progeria/pathology , Brain/pathology , Central Nervous System/pathology , Cerebellum/pathology , Child, Preschool , Demyelinating Diseases/pathology , Diffuse Cerebral Sclerosis of Schilder/pathology , Female , Humans , Infant, Newborn , Mesencephalon/pathology , Occipital Lobe/pathology , Staining and Labeling , SyndromeSubject(s)
Chromosome Aberrations/genetics , Genes, Dominant , Pierre Robin Syndrome/genetics , Adult , Child, Preschool , Chromosome Disorders , Female , Humans , Infant, Newborn , MaleABSTRACT
A 4-year-old girl is reported with a neonatally apparent progeroid syndrome. Parenteral consanguinity indicates autosomal recessive inheritance. Psychomotor development and physical growth are severely deficient. Mainly characterized by congenital absence of subcutaneous fat tissue, this child is very similar to four patients reported earlier and recognized as representing a newly delineated clinical entity, called here the Wiedemann-Rautenstrauch or neonatal progeroid syndrome.
Subject(s)
Infant, Newborn, Diseases/genetics , Progeria/genetics , Child, Preschool , Consanguinity , Female , Growth Disorders/complications , Growth Disorders/genetics , Humans , Infant , Infant, Newborn , Progeria/complications , Psychomotor Disorders/complications , Psychomotor Disorders/genetics , SyndromeABSTRACT
A two-year-old girl with spondylocostal dysostosis and urinary tract anomalies is described. Genetic counselling to the healthy non-consanguineous parents is based on the hypothesis of autosomal recessive inheritance. At birth this type of spondylocostal dysostosis can be differentiated radiographically from related conditions by the severe and generalized anomaly of the entire vertebral column, and by the typical configuration of the posteriorly-fused ribs. Only the cardinal clinical features of a short trunk and a short, immobile neck are consistently present in all patients. In one group of patients the severe thoracic malformation and lordosis contribute to cardiopulmonary problems with a fatal outcome in early infancy. The roentgenographic changes are less marked in other patients, whose subsequent clinical course is usually without major problems but remains at present insufficiently known.
