Platelet-derived Growth Factor Receptor Gene Research Articles

Current treatment strategies and future perspectives for gastrointestinal stromal tumors.

Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors that originate from the gastrointestinal tract, mostly from the stomach. GISTs are derived from the myenteric interstitial cells of Cajal and are caused by several mutations in the c-kit and platelet-derived growth factor receptor genes. Clinically, GISTs are detected by endoscopic and imaging findings and are diagnosed by immunostaining. Surgery is the first line of treatment, and if the tumor is relatively small, minimally invasive surgery such as laparoscopy is performed. In recent years, neoadjuvant therapy has been administered to patients with GISTs that are suspected of having a large size or infiltration to other organs. Postoperative adjuvant imatinib is the standard therapy for high-risk GISTs. It is important to assess the risk of recurrence after GIST resection. However, the effect of tyrosine kinase inhibitor use will vary by the mutation of c-kit genes and the site of mutation. Furthermore, information regarding gene mutation is indispensable when considering the treatment policy for recurrent GISTs. This article reviews the clinicopathological characteristics of GISTs along with the minimally invasive and multidisciplinary treatment options available for these tumors. The future perspectives for diagnostic and treatment approaches for these tumors have also been discussed.

Correlation between mutational status and survival and second cancer risk assessment in patients with gastrointestinal stromal tumors: a population-based study.

BackgroundGastrointestinal stromal tumors are sarcomas of the digestive tract characterized by mutations mainly located in the c-KIT or in the platelet-derived growth factor receptor (PDGFR)-alpha genes. Mutations in the BRAF gene have also been described. Our purpose is to define the distribution of c-KIT, PDGFR and BRAF mutations in a population-based cohort of gastrointestinal stromal tumors (GIST) patients and correlate them with anatomical site, risk classification and survival. In addition, as most of the GIST patients have a long survival, second cancers are frequently diagnosed in them. We performed a second primary cancer risk assessment.MethodsOur analysis was based on data from Tarragona and Girona Cancer Registries. We identified all GIST diagnosed from 1996 to 2006 and performed a mutational analysis of those in which paraffin-embedded tissue was obtained. Observed (OS) and relative survival (RS) were calculated according to risk classifications and mutational status. Multivariate analysis of variables for observed survival and was also done.ResultsA total of 132 GIST cases were found and we analyzed mutations in 108 cases. We obtained 53.7% of mutations in exon 11 and 7.4% in exon 9 of c-KIT gene; 12% in exon 18 and 1.9% in exon 12 of PDGFR gene and 25% of cases were wild type GIST. Patients with mutations in exon 11 of the c-KIT gene had a 5-year OS and RS of 59.6% and 66.3%, respectively. Patients with mutations in exon 18 of the PDGFR gene had a 5-year OS and RS of 84.6% and 89.7%. In multivariate analysis, only age and risk group achieved statistical significance for observed survival. GIST patients had an increased risk of second cancer with a hazard ratio of 2.47.ConclusionsThis population-based study shows a spectrum of mutations in the c-KIT and PDGFR genes in GIST patients similar to that previously published. The OS and RS of GIST with the exon 18 PDGFR gene mutation could indicate that this subgroup of patients may be less aggressive and have a good prognosis, although less sensitive to treatment at recurrence. In our study, GIST patients have an increased risk of developing a second neoplasm.

Inflammatory fibroid polyp (Vanek’s polyp): a case report and literature review

Inflammatory fibroid polyp (IFP) is a benign uncommon lesion (1%-4% of gastric benign lesions), originated from the submucosa of the gastrointestinal tract. Its origin is controversial and immunohistochemical studies of lesions have largely refuted the possible vascular, neural or smooth muscle origin. Recent studies suggest a neoplastic etiology due to a mutation, in some cases, in the alpha-type platelet-derived growth factor receptor gene (PDGFRa). Our objective is to report the case of a patient aged 70 years, with gastric IFP, comparing her immunohistochemical profile with those of other studies, and a brief review of the literature.

Reduced platelet-derived growth factor receptor expression is a primary feature of human bronchopulmonary dysplasia.

Animal studies have shown that platelet-derived growth factor (PDGF) signaling is required for normal alveolarization. Changes in PDGF receptor (PDGFR) expression in infants with bronchopulmonary dysplasia (BPD), a disease of hypoalveolarization, have not been examined. We hypothesized that PDGFR expression is reduced in neonatal lung mesenchymal stromal cells (MSCs) from infants who develop BPD. MSCs from tracheal aspirates of premature infants requiring mechanical ventilation in the first week of life were studied. MSC migration was assessed in a Boyden chamber. Human lung tissue was obtained from the University of Rochester Neonatal Lung Biorepository. Neonatal mice were exposed to air or 75% oxygen for 14 days. PDGFR expression was quantified by qPCR, immunoblotting, and stereology. MSCs were isolated from 25 neonates (mean gestational age 27.7 wk); 13 developed BPD and 12 did not. MSCs from infants who develop BPD showed lower PDGFR-α and PDGFR-β mRNA and protein expression and decreased migration to PDGF isoforms. Lungs from infants dying with BPD show thickened alveolar walls and paucity of PDGFR-α-positive cells in the dysmorphic alveolar septa. Similarly, lungs from hyperoxia-exposed neonatal mice showed lower expression of PDGFR-α and PDGFR-β, with significant reductions in the volume of PDGFR-α-positive alveolar tips. In conclusion, MSCs from infants who develop BPD hold stable alterations in PDGFR gene expression that favor hypoalveolarization. These data demonstrate that defective PDGFR signaling is a primary feature of human BPD.

Critical Role of the Platelet-derived Growth Factor Receptor (PDGFR) β Transmembrane Domain in the TEL-PDGFRβ Cytosolic Oncoprotein

The fusion of TEL with platelet-derived growth factor receptor (PDGFR) beta (TPbeta) is found in a subset of patients with atypical myeloid neoplasms associated with eosinophilia and is the archetype of a larger group of hybrid receptors that are produced by rearrangements of PDGFR genes. TPbeta is activated by oligomerization mediated by the pointed domain of TEL/ETV6, leading to constitutive activation of the PDGFRbeta kinase domain. The receptor transmembrane (TM) domain is retained in TPbeta and in most of the described PDGFRbeta hybrids. Deletion of the TM domain (DeltaTM-TPbeta) strongly impaired the ability of TPbeta to sustain growth factor-independent cell proliferation. We confirmed that TPbeta resides in the cytosol, indicating that the PDGFRbeta TM domain does not act as a transmembrane domain in the context of the hybrid receptor but has a completely different function. The DeltaTM-TPbeta protein was expressed at a lower level because of increased degradation. It could form oligomers, was phosphorylated at a slightly higher level, co-immunoprecipitated with the p85 adaptor protein, but showed a much reduced capacity to activate STAT5 and ERK1/2 in Ba/F3 cells, compared with TPbeta. In an in vitro kinase assay, DeltaTM-TPbeta was more active than TPbeta and less sensitive to imatinib, a PDGFR inhibitor. In conclusion, we show that the TM domain is required for TPbeta-mediated signaling and proliferation, suggesting that the activation of the PDGFRbeta kinase domain is not enough for cell transformation.

Accidental and Intentional Overdose of Imatinib: a Report of Outcome and Side Effect of 46 Cases.

Abstract 4273 BackgroundIn the initial phase I trials maximum tolerated dose with imatinib was not reached. However based on the clinical results, imatinib at doses of 400 mg to 800 mg has been registered for the treatment of various malignancies such as adult and paediatric patients (pts) with newly diagnosed chronic myeloid leukaemia (CML) or CML in blast crisis, accelerated phase, or in chronic phase after IFN-failure, adult pts with Ph+ acute lymphoblastic leukaemia, myelodysplastic/myeloproliferative diseases associated with platelet-derived growth factor receptor gene re-arrangements, systemic mastocytosis, hypereosinophilic syndrome, malignant gastrointestinal stromal tumours or dermatofibrosarcoma protuberans. Using the recommended doses of 400 to 800 mg for adults and 340 mg/m2 of body surface area for children, a number of hematological and non-hematological side-effects with imatinib have been reported which are more common with higher doses and easily manageable. Clinical experience with dose of imatinib higher than that recommended is limited. There are isolated cases of overdose reported in the literature. Suicidal attempt or accidental overdoses are the main causes of overdose. The management of theses cases is proposed based on this preliminary report. MethodsA cumulative search of the Novartis ARGUS safety database was performed with a cut off date of April 2008 and revealed 125 cases of overdose, out of which 30 cases had minimal information, another 25 cases were determined to be therapeutic or prescribed doses and 26 cases were overdose related to concomitant drugs known to increase the plasma concentration. Out off the 46 cases selected for this analysis, 38 were spontaneous reports, 5 were clinical trial reports, 2 were literature reports and 1 a personal case (Dr F Millot). ResultsFour subcategories of overdose are described: accidental overdose adults cases (n=22) (In 21 reports overdose was due to intake of 400 mg instead of 100 mg).; intentional overdose adult's cases (n=11); unknown type of overdose adults cases (n=6) and accidental overdose paediatric cases n=7). Adult overdose side effect :1,200 to 1,600 mg (duration varying between 1 to 10 days): nausea, vomiting, diarrhoea, rash, erythema, oedema, swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain, headache, decreased appetite; 1,800 to 3,200 mg (as high as 3,200 mg daily for 6 days): weakness, myalgia, increased CPK, increased bilirubin, gastrointestinal pain. The literature reported one pt who experienced nausea, vomiting, abdominal pain, pyrexia, facial swelling, neutrophil count decreased, increased transaminases after the absorption of 6,400 mg (single dose). Other pts took 8 to 10 g (single dose): vomiting and gastrointestinal pain have been reported. Attempts of suicide was the reason for overdose for 11 pts with doses ranging from 800 mg to 10 000 mg; the outcome was satisfactory for all pts. One 20 year old girl attempted suicide with the absorption of 2.4 grams. Plasma concentration was monitored several days with a maximum concentration of 2381 ng/ml. Imatinib was then resumed at 400 mg. In 6 cases the reason for taking overdose was unknown: 5 cases took 1600 mg (in all these cases pts mistook 400 mg in place of 100 mg 4 time per day), I additional case was a 14 year old girl who adsorbed 4 grams without effect. The final set of pts is paediatric cases (n=7). One 3 year-old male exposed to a single dose of 400 mg experienced vomiting, diarrhoea and anorexia and another 3 year old male exposed to a single dose of 980 mg dose experienced decreased white blood cell count and diarrhea. ConclusionWith the limited experience available following overdose of imatinib, most of the pts had complete recovery. Even with dose up to 10 grams the outcome was good. In the event of overdose, pts should be closely observed and appropriate symptomatic care administered. Suicide risk assessment should be performed. In addition to clinical support, monitoring with frequent blood counts, renal and liver function measurements should be performed. Intravenous fluids to maintain hydration and imatinib plasma monitoring might be considered, if available. Based on these reports there is no need for hematopoietic growth factors. Disclosures:Hatfield:Pharmaceuticals Corporation: Employment, Equity Ownership, Patents & Royalties. Cui:Pharmaceuticals Corporation: Employment.

Prognostic Significance of Stromal Platelet-Derived Growth Factor β-Receptor Expression in Human Breast Cancer

Prognostic Significance of Stromal Platelet-Derived Growth Factor β-Receptor Expression in Human Breast Cancer

Vasculopathic Changes, a Somatostatin-Producing Neuroendocrine Carcinoma and a Jejunal Gastrointestinal Stromal Tumor in a Patient with Type 1 Neurofibromatosis

A 36-year-old male with neurofibromatosis type 1 (NF-1) presented with symptoms of obstructive jaundice. Imaging showed a periampullary mass, which on endoscopic retrograde cholangiopancreatography biopsy proved to be a somatostatinoma. A Whipple's procedure was performed and a somatostatinoma of the duodenum was confirmed. In addition, the patient had a gastrointestinal stromal tumor (GIST) of the jejunum with accompanying hyperplasia of interstitial cells of Cajal. The somatostatinoma was histologically characteristic with pseudoglandular and solid patterns together with psammoma bodies and lymphovascular invasion. The GIST did not display mutations in c-kit or platelet-derived growth factor receptor genes. The novel finding in this case was the presence of several vessels in the submucosa and muscularis propria of the duodenum displaying prominent intimal hyperplasia and in keeping with so-called neurofibromatosis-associated vasculopathy. These abnormal vessels were within and close to the somatostatinoma only and were not found away from the tumor. It is thought that the vasculopathy is related to NF-1 with abnormal neurofibromin possibly playing a role.

Prognosis, Imatinib Dose, and Benefit of Sunitinib in GIST: Knowing the Genotype

Prognosis, Imatinib Dose, and Benefit of Sunitinib in GIST: Knowing the Genotype

C-reactive protein and vein graft disease: evidence for a direct effect on smooth muscle cell phenotype via modulation of PDGF receptor-β

Plasma C-reactive protein (CRP) concentration is a biomarker of systemic atherosclerosis and may also be associated with vein graft disease. It remains unclear whether CRP is also an important modulator of biological events in the vessel wall. We hypothesized that CRP influences vein graft healing by stimulating smooth muscle cells (SMCs) to undergo a phenotypic switch. Distribution of CRP was examined by immunohistochemistry in prebypass human saphenous veins (HSVs, n = 21) and failing vein grafts (n = 18, 25-4,400 days postoperatively). Quiescent HSV SMCs were stimulated with human CRP (5-50 microg/ml). SMC migration was assessed in modified Boyden chambers with platelet-derived growth factor (PDGF)-BB (5-10 ng/ml) as the chemoattractant. SMC viability and proliferation were assessed by trypan blue exclusion and reduction of Alamar Blue substrate, respectively. Expression of PDGF ligand and receptor (PDGFR) genes was examined at RNA and protein levels after 24-72 h of CRP exposure. CRP staining was present in 13 of 18 diseased vein grafts, where it localized to the deep media and adventitia, but it was minimally detectable in most prebypass veins. SMCs pretreated with CRP demonstrated a dose-dependent increase in migration to PDGF-BB (P = 0.02), which was inhibited by a PDGF-neutralizing antibody. SMCs treated with CRP showed a dose-dependent increase in PDGFRbeta expression and phosphorylation after 24-48 h. Exogenous CRP had no effect on SMC viability or proliferation. These data suggest that CRP is detectable within the wall of most diseased vein grafts, where it may exert local effects. Clinically relevant levels of CRP can stimulate SMC migration by a mechanism that may involve upregulation and activation of PDGFRbeta.

Differential Behaviors of Atrial Versus Ventricular Fibroblasts

In various heart disease paradigms, atria show stronger fibrotic responses than ventricles. The possibility that atrial and ventricular fibroblasts respond differentially to pathological stimuli has not been examined. We compared various morphological, secretory, and proliferative response indexes of canine atrial versus ventricular fibroblasts. Cultured atrial fibroblasts showed faster cell surface area increases, distinct morphology at confluence, and greater alpha-smooth muscle actin expression than ventricular fibroblasts. Atrial fibroblast proliferation ([(3)H]thymidine incorporation) responses were consistently greater for a range of growth factors, including fetal bovine serum, platelet-derived growth factor (PDGF), basic fibroblast growth factor, angiotensin II, endothelin-1, and transforming growth factor-beta(1). Normal atrial tissue showed larger myofibroblast density compared with ventricular tissue, and the difference was exaggerated by congestive heart failure. Congestive heart failure atria showed larger fractions of fibroblasts in mitotic phases compared with ventricles and displayed enhanced gene expression of fibroblast-selective markers (collagen-1, collagen-3, fibronectin-1). Gene microarrays revealed 225 differentially expressed transcript probe sets between paired atrial and ventricular fibroblast samples, including extracellular matrix (eg, fibronectin, laminin, fibulin), cell signaling (PDGF, PDGF receptor, angiopoietin, vascular endothelial growth factor), structure (keratin), and metabolism (xanthine dehydrogenase) genes, identifying PDGF as a candidate contributor to atrial-ventricular fibroblast differences. PDGF receptor gene expression was greater in normal atrium compared with ventricle, and congestive heart failure differentially enhanced atrial versus ventricular PDGF and PDGF receptor gene expression. PDGF receptor protein expression and alpha-smooth muscle actin protein expression were enhanced in isolated congestive heart failure fibroblasts. The PDGF receptor tyrosine kinase inhibitor AG1295 eliminated fetal bovine serum- and transforming growth factor-beta(1)-stimulated atrial-ventricular fibroblast proliferative response differences. Atrial fibroblasts behave differently than ventricular fibroblasts over a range of in vitro and in vivo paradigms, with atrial fibroblasts showing enhanced reactivity that may explain greater atrial fibrotic responses. PDGF signaling is particularly important for atrium-selective fibroblast responses and may represent a novel target for arrhythmogenic atrial structural remodeling prevention.

PDGF‐A as an epicardial mitogen during heart development

In the developing heart, reciprocal interactions between the epicardium and myocardium drive further sublineage specification and ventricular chamber morphogenesis. Several observations suggest that the epicardium is a source of secreted factors that influence cardiomyocyte proliferation, and these factors may have other roles as well. However, the identity of these epicardial factors remains mostly unknown. We have identified platelet-derived growth factor-A (PDGF-A) as one of several mitogens expressed by the rat EMC epicardial cell line (epicardial mesothelial cells), by embryonic epicardium and myocardium during mouse heart development, and by adult epicardium. Expression of the cognate receptor gene Pdgfra was detected in the epicardium, although a low level of expression in myocardium could not be ruled out. To address the potential role of PDGF signaling in heart development, we mutated both PDGF receptor genes in the myocardial and mesodermal compartments of the heart; however, this did not result in an observable cardiac phenotype. This finding suggests that mesodermal PDGF signaling is not essential in heart development, although its role may be redundant with other signaling pathways. Indeed, our results demonstrate the presence of additional mitogens that may have such an overlapping role.

Successful Treatment of Chronic Myeloproliferative Disease-unclassifiable (CMPD-U) with No Chromosomal Abnormalities by Imatinib Mesylate

We report a chronic myeloproliferative disease-unclassifiable (CMPD-U) patient who achieved hematological remission following imatinib mesylate (imatinib). Chromosomal and molecular analyses demonstrated no genetic abnormalities of c-abl, bcr-abl, c-kit or platelet-derived growth factor receptor (PDGFR) genes from hematopoietic cells. Although there has been one report of CMPD-U patient with chromosomal abnormalities of the PDGFR gene having complete hematologic responses upon treatment with imatinib, there have not been similar reports of patients without chromosomal abnormalities. This is the first case report of a CMPD-U patient with no chromosomal abnormalities who completely responded to treatment with imatinib.

Characterization of three new imatinib-responsive fusion genes in chronic myeloproliferative disorders generated by disruption of the platelet-derived growth factor receptor gene

We sought to identify new fusion genes with involvement of the platelet-derived growth factor receptor beta gene (PDGFRB) in three patients presenting with various subtypes of chronic myeloproliferative disorders associated with chromosomal aberrations involving chromosome bands 5q31-33. We performed 5 rapid amplification of cDNA ends (5 -RACE)-polymerase chain reaction (PCR) with RNA/cDNA derived from a patient (case #1) with a t(5;12)(q31-33;q24) and a second patient (case #2) with a complex rearrangement involving chromosomes 1, 5 and 11. A newly developed DNA-based long-distance inverse PCR (LDI-PCR) was performed on a third patient (case #3) with a t(4;5;5)(q23;q31;q33). In cases #1 and #2, we identified mRNA fusions between GIT2 exon 12 and GPIAP1 exon 7, respectively, and PDGFRB exon 11. In case #3, LDI-PCR revealed a fusion between PRKG2 exon 5 and a truncated PDGFRB exon 12. The region encoding the catalytic domain of PDGFRbeta is retained in all three cases, with the partner contributing a coiled-coil domain (GPIAP1, PRKG2) or an ankyrin protein interaction motif (GIT2) that may potentially lead to dimerization and constitutive activation of the fusion proteins. Treatment with imatinib (400 mg/day) has led to sustained complete hematologic remission in all three patients. These data provide further evidence that numerous partner genes fuse to PDGFRB in BCR-ABL negative chronic myeloproliferative disorders. Although these fusion genes occur rarely, their identification is essential in order to detect patients in whom targeted treatment with tyrosine kinase inhibitors is likely to be successful.

Target Marker Gene Expressions and the Possibility of Molecular Therapy for Children's Brain Tumors.

ErbB2, c-Myc and p53 gene expressions are widely reported for the poor prognostic markers for medulloblastoma (MB) patients. Recently, Wnt pathway and Sonic Hedgehog (SHH) pathways are known to related to the oncogenesis of MB cells, and the PDGF receptor gene and some adhesion molecule gene expressions are also known to the markers of the dissemination or the metastasis of MB cells. For adult malignant brain tumors, the molecular targeted therapy of the antibody (trastuzumab, cetuximab), the tyrosine kinase inhibitor (imatinib, gefinitib) or other signal transduction inhibitor (cyclopamin) are clinically researched. We examined several important marker gene expressions of the molecular therapy in various children's brain tumors and searched the possible molecular targeted therapy.[Materials and methods] Fifteen children's brain tumor (five MB, seven glioma, three ependymoma) and four adult brain tumor (two glioma, two glioblastoma) were examind. The three MB cases were primary metaststic ones. The mRNA expressions of the marker genes (ErbB2, PDGF receptor, PCNA, SPARC, β-catenin, SUFU, c-Myc, p53, TrkC and so on) were examined by quantity polymerase chain (qPCR) reaction with fresh frozen tumor cells. For the normal control, we used the normal cerebellum total RNA samples of the Becton, Dikinson and Company. CYBR green coloring system was used for the qPCR and their primers were designed in the region between two exons. GAPDH gene expression was also examined as an internal control and all of the gene expression were normalized by GAPDH expression.[Results] ErbB2 gene expression in MB cells were various, but their expression were similar to clinical futures, such as, the higher expressed cases had some high risk factors. In glioma cells, ErbB2 gene expression were almost equal by lower levels. PDGF receptor gene expression were more than five to ten times elevated in all of the glioma cells, even if they were low grade malignancy glioma, and were higher than that in MB cells. PCNA was specially elevated in primary metastatic MB cells.[Conclusion] Our data shows that the molecular characteristics of the children's brain tumors were thought to be different by cases, even if they had same histopathological characters. Some special gene tageting therapy, such as anti-ErbB2, PDGFR and/or PCNA therapy can be used for the various children's brain tumors which are resistant for conventional therapies and are cured by adequate molecular therapy.

A c-kit-Negative Gastrointestinal Stromal Tumor With a Platelet-Derived Growth Factor Receptor Alpha Mutation

Gastrointestinal stromal tumors (GISTs) are well-recognized mesenchymal neoplasms of the intestinal tract. A diagnosis of GIST is not always possible using IHC techniques for detection of c-kit. The authors describe a 64-year-old man who presented with an upper abdominal quadrant mass. Histology showed a predominantly epithelioid neoplasm with focal "spindle cell" areas. IHC studies were positive for muscle markers and negative for c-kit. The morphologic and immunophenotypic appearance could be compatible with either a smooth muscle tumor or a GIST. Because of the differences in treatment protocols and prognosis between these two entities, molecular studies to detect c-kit or platelet-derived growth factor receptor (PDGFR) activating mutations were performed. No mutations were found in the c-kit gene, but a mutation was detected in the PDGFR gene. This additional molecular study allowed the authors to formulate the precise diagnosis of a c-kit-negative GIST with strong smooth muscle marker expression.

Imatinib mesylate as a novel treatment option for hypereosinophilic syndrome: two case reports and a comprehensive review of the literature

Hypereosinophilic syndromes (HES) are a heterogenous group of rare disorders characterized by sustained and otherwise unexplained overproduction of eosinophils with organ involvement and consecutive dysfunction. Recent reports document the efficacy of imatinib mesylate in a large proportion of HES patients (65%). Rearrangements involving the platelet-derived growth factor receptor genes (PDGFRA and PDGFRB), both tyrosine kinase receptors, have been demonstrated to be pathogenetically linked to the dysregulated clonal overproduction of eosinophils. This refined hypothesis has been confirmed by the discovery of the novel FIP1L1-PDGFRA fusion gene, which is a gain-of-function gene on chromosome 4q12. Its product is an imatinib-sensitive tyrosine kinase, which can be found in a subset of patients with HES, particularly in those responding to treatment with imatinib mesylate. Here, we sum up recent knowledge of clinical features, pathophysiology and novel treatment aspects of HES by performing a comprehensive search of the available literature and report on 94 patients. We particularly address the issue of organ involvement and specific characteristics of the variable clinical pictures. In addition, two cases will be presented, which illustrate typical clinical scenarios and treatment outcome.

Response to Imatinib Mesylate in a Patient with Idiopathic Hypereosinophilic Syndrome Associated with Cyclic Eosinophil Oscillations

A 26-year-old man with idiopathic hypereosinophilic syndrome (HES) was treated with imatinib mesylate following a 5-year history of prednisolone therapy. The patient had hypereosinophilia (absolute eosinophil counts >1500/microL) occurring in cyclic oscillations as well as histologically diagnosed eosinophilic vasculitis, bursitis, and periodic soft-tissue swellings. Laboratory data revealed high levels of serum tryptase and increased numbers of mast cells in the bone marrow, but serum interleukin 5 levels were within the normal range. The disease initially responded well to 100 mg/day of imatinib mesylate but recurred 8 weeks later. Thereafter, a daily 200-mg dose was temporarily effective. Despite the response to imatinib, the FIP1L1-PDGFRA fusion gene was not detected by fluorescence in situ hybridization analysis. Additional molecular and cytogenetic studies showed neither translocations of platelet-derived growth factor receptor (PDGFR) genes nor mutations in the c-KIT or the PDGFR genes. Although imatinib mesylate is a choice of treatment for patients with HES, its precise molecular mechanism in individual cases remains to be clarified.

Blood Eosinophilia: A New Paradigm in Disease Classification, Diagnosis, and Treatment

Acquired blood eosinophilia is considered either a primary or a secondary phenomenon. Causes of secondary (ie, reactive) eosinophilia include tissue-invasive parasitosis, allergic or inflammatory conditions, and malignancies in which eosinophils are not considered part of the neoplastic process. Primary eosinophilia is classified operationally into 2 categories: clonal and idiopathic. Clonal eosinophilia stipulates the presence of either cytogenetic evidence or bone marrow histological evidence of an otherwise classified hematologic malignancy such as acute leukemia or a chronic myeloid disorder. Idiopathic eosinophilia is a diagnosis of exclusion (ie, not secondary or clonal). Hypereosinophilic syndrome is a subcategory of idiopathic eosinophilia; diagnosis requires documentation of both sustained eosinophilia (absolute eosinophil count > or = 1500 cells/microL for at least 6 months) and target organ damage (eg, involvement of the heart, lung, skin, or nerve tissue). Genetic mutations involving the platelet-derived growth factor receptor genes (PDGFR-alpha and PDGFR-beta) have been pathogenetically linked to clonal eosinophilia, and their presence predicts treatment response to imatinib. Accordingly, cytogenetic and/or molecular investigations for the presence of an imatinib-sensitive molecular target should accompany current evaluation for primary eosinophilia. In the absence of such a drug target, specific treatment is dictated by the underlying hematologic malignancy in cases of clonal eosinophilia; however, the initial treatment of choice for symptomatic patients with hypereosinophilic syndrome is prednisone and/or interferon alfa.

Development of hygromas or severe edema during treatment with the tyrosine kinase inhibitor STI571 is not associated with platelet-derived growth factor receptor (PDGFR) gene polymorphisms

STI571 is active against Bcr/Abl-, c-kit- and platelet-derived growth factor receptor (PDGFR)-driven malignancies. Mild to moderate edema is common, whereas severe edema, body cavity effusions and subdural hygromas are rarely observed. These effects have been suggested to involve inhibition of PDGFR signaling, but predisposing factors are unknown. We examined SNPs in the PDGFR alpha and beta gene regions in STI571-treated patients with and without life-threatening edema or cerebral hygromas, and in healthy volunteers. By RFLP analysis of 15 SNPs, the frequencies of genotypes did not differ between the three groups. SNPs of PDGFR genes do not appear to play a role in patient’s susceptibility to clinically severe edema formation during treatment with STI571.