ABSTRACT: Well-differentiated fetal adenocarcinoma (WDFA) is a rare pulmonary malignancy. Biomarkers of tumor biology has rarely been studied in WDFA. Here, we report two WDFA patients. Both patients had blood-streaked sputum or mild hemoptysis at presentation. They underwent lobectomy and systematic mediastinal lymphadenectomy. Expression of PDGFR? on the plasma membrane was demonstrated by immunohistochemistry (IHC) in the resected tumor specimens. Further IHC examination showed intense immunostaining of ?-catenin in both patients but negative staining for TP53, CEA, CD56, EGFR, CK5/6, HER2, S-100, ER, PR, BCL2, and NSE. Both patients had no recurrence to date after more than 3 years of follow up. Herein, we reviewed this rare disease with special emphasis on the clinico-pathological features, treatment and potential role of PDGFR?.
Project description:BACKGROUND:Massive hemoptysis is a life-threatening condition. Massive hemoptysis caused by pulmonary vein stenosis (PVS) after radiofrequency catheter ablation for atrial fibrillation (AF) is rare. However, bilateral lung hemorrhage following bilateral PVS is extremely rare. CASE PRESENTATION:We herein describe a 62-year-old man with refractory massive hemoptysis after radiofrequency catheter ablation for AF, which was successfully controlled by surgical lobectomy and endovascular bilateral PV stenting. The hemorrhage was derived from the bilateral lungs following PV obstruction and bilateral PVS, which was definitively diagnosed by bronchoscopic examination. The patient had no recurrence of hemoptysis during a follow-up period of 30 months, and the PV stents had not narrowed as shown by computed tomography 30 months after stent placement. CONCLUSIONS:Massive hemoptysis can be caused by bilateral PVS after radiofrequency catheter ablation for AF, and hemorrhage from the bilateral lungs in such patients is extremely rare. Nevertheless, cardiologists, interventional radiologists, and pulmonologists should consider the potential for massive hemoptysis caused by PVS.
Project description:CASTLE (Carcinoma showing thymus-like elements) is a rare malignant neoplasm of the thyroid resembling lymphoepithelioma-like and squamous cell carcinoma of the thymus with different biological behaviour and a better prognosis than anaplastic carcinoma of the thyroid.We retrospectively investigated 6 cases of this very rare neoplasm in order to investigate the mutational status of KRAS, EGFR, PDGFR-? and KIT, as well as the immunohistochemical expression pattern of CD117, EGFR and COX-2, and possibly find new therapeutic targets.Diagnosis was confirmed by a moderate to strong expression of CD5, CD117 and CK5/6, whereas thyroglobulin, calcitonin and TTF-1 were negative in all cases. Tumors were also positive for COX-2 and in nearly all cases for EGFR. In four cases single nucleotide polymorphisms (SNPs) could be detected in exon 12 of the PDGFR-? gene (rs1873778), in three cases SNPs were found in exon 20 of the EGFR gene (rs1050171). No mutations were found in the KIT and KRAS gene.All tumors showed a COX-2 expression as well as an EGFR expression except for one case and a wild-type KRAS status. No activating mutations in the EGFR, KIT and PDGFR-? gene could be detected. Our data may indicate a potential for targeted therapies, but if these therapeutic strategies are of benefit in CASTLE remains to be determined.The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1658499296115016.
Project description:Genetic profiling studies on muscle-invasive bladder cancers (MIBCs) have discovered molecular subtypes with different biological characteristics. Immunohistochemical (IHC) markers such as GATA3, cytokeratin (CK) 20, CK5/6, and p53 are associated with these subtypes. In this study, we investigated the biological and prognostic significance of these IHC markers in MIBCs from 91 patients who underwent radical cystectomy. High Ki-67 indices were associated with negative CK20 (p = 0.002) and diffuse CK5/6 (p = 0.001) staining. By contrast, tumors with diffuse GATA3 expression had low Ki-67 index (p = 0.006). Regarding p53, three staining patterns were associated with a high Ki-67 index: (1) complete absence, (2) diffusely strong nuclear reactivity, and (3) diffusely strong cytoplasmic staining (p < 0.001 compared with other patterns). CK5/6 and CK20 expression was typically present in a reciprocal fashion; however, diffuse GATA3 and CK5/6 coexpression was observed in 13 (14.29%) cases. Among 78 chemotherapy-naïve patients, low GATA3 staining was associated with worse recurrence-free survival in both univariate (p = 0.008) and multivariate analyses (p = 0.002). CK20, CK5/6, or p53 expression was not associated with clinical outcome. Based on our results, IHC staining for GATA3 may help risk stratification in patients with MIBC receiving radical cystectomy. In addition, the differences in Ki-67 indices suggested that aberrant p53 expression was better defined by the three aforementioned patterns, rather than percentage of nuclear staining alone.
Project description:BACKGROUND:Platelet derived growth factor receptor alpha (PDGFR?) has been considered as a relevant factor in tumor proliferation, angiogenesis and metastatic dissemination. It was a target of tyrosine kinase (TK) inhibitors emerged in the therapy of diverse cancers. In colorectal cancer, the commonly used therapy is anti-epithelial growth factor receptor (EGFR). However, both RAS mutated and a subgroup of RAS wild type patients resist to such therapy. The aim of this study is to investigate PDGFR? protein expression and mutational status in colorectal adenocarcinoma and their association with clinicopathological features and molecular RAS status to provide useful information for the identification of an effective biomarker that might be implicated in prognosis and treatment prediction. METHODS:Our study enrolled 103 formalin fixed paraffin-embedded (FFPE) colorectal adenocarcinoma. PDGFR? expression was investigated by immunohistochemistry (IHC). Hotspot exon 18 of PDGFRA was studied by PCR followed by Sanger sequencing and RAS status was determined by real time quantitative PCR. Thirteen normal colon tissues were used as negative controls. RESULTS:PDGFR? staining was detected in the cytoplasm of all tissues. Low expression was observed in all normal colon mucosa. In adenocarcinoma, 45% (45/100) of cases showed PDGFR? overexpression. This overexpression was significantly associated with mutations in exon 18 (P?=?0.024), RAS wild type status (P?<?10-3), tumor diameter (P?=?0.048), whereas there was no association with tumor side (P?=?0.13) and other clinicopathological features. CONCLUSION:Overexpression of PDGFR? in adenocarcinoma suggests its potential role in tumor cells growth and invasion. The association between PDGFR? overexpression in both tumor and stromal adenocarcinoma cells with RAS wild type status suggests its potential role in anti-EGFR therapy resistance and the relevance of using it as specific or adjuvant therapeutic target.
Project description:Cardiac progenitor/stem cells in adult hearts represent an attractive therapeutic target for heart regeneration, though (inter)-relationships among reported cells remain obscure. Using single-cell qRT-PCR and clonal analyses, here we define four subpopulations of cardiac progenitor/stem cells in adult mouse myocardium all sharing stem cell antigen-1 (Sca1), based on side population (SP) phenotype, PECAM-1 (CD31) and platelet-derived growth factor receptor-? (PDGFR?) expression. SP status predicts clonogenicity and cardiogenic gene expression (Gata4/6, Hand2 and Tbx5/20), properties segregating more specifically to PDGFR?(+) cells. Clonal progeny of single Sca1(+) SP cells show cardiomyocyte, endothelial and smooth muscle lineage potential after cardiac grafting, augmenting cardiac function although durable engraftment is rare. PDGFR?(-) cells are characterized by Kdr/Flk1, Cdh5, CD31 and lack of clonogenicity. PDGFR?(+)/CD31(-) cells derive from cells formerly expressing Mesp1, Nkx2-5, Isl1, Gata5 and Wt1, distinct from PDGFR?(-)/CD31(+) cells (Gata5 low; Flk1 and Tie2 high). Thus, PDGFR? demarcates the clonogenic cardiogenic Sca1(+) stem/progenitor cell.
Project description:Platelet-derived growth factor (PDGF) receptors (PDGFR) and their ligands play critical roles in several human malignancies. Sunitinib is a clinically approved multitargeted tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptor, c-KIT, and PDGFR, and has shown clinical activity in various solid tumors. Activation of PDGFR signaling has been described in gastrointestinal stromal tumors (PDGFRA mutations) as well as in chronic myeloid leukemia (BCR-PDGFRA translocation), and sunitinib can yield clinical benefit in both settings. However, the discovery of PDGFR activating mutations or gene rearrangements in other tumor types could reveal additional patient populations who might benefit from treatment with anti-PDGFR therapies, such as sunitinib. Using a high-throughput cancer cell line screening platform, we found that only 2 of 637 tested human tumor-derived cell lines show significant sensitivity to single-agent sunitinib exposure. These two cell lines [a non-small-cell lung cancer (NSCLC) and a rhabdomyosarcoma] showed expression of highly phosphorylated PDGFRA. In the sunitinib-sensitive adenosquamous NSCLC cell line, PDGFRA expression was associated with focal PFGRA gene amplification, which was similarly detected in a small fraction of squamous cell NSCLC primary tumor specimens. Moreover, in this NSCLC cell line, focal amplification of the gene encoding the PDGFR ligand PDGFC was also detected, and silencing PDGFRA or PDGFC expression by RNA interference inhibited proliferation. A similar codependency on PDGFRA and PDGFC was observed in the sunitinib-sensitive rhabdomyosarcoma cell line. These findings suggest that, in addition to gastrointestinal stromal tumors, rare tumors that show PDGFC-mediated PDGFRA activation may also be clinically responsive to pharmacologic PDGFRA or PDGFC inhibition.
Project description:Activated forms of the platelet derived growth factor receptor alpha (PDGFR?) have been described in various tumors, including FIP1L1-PDGFR? in patients with myeloproliferative diseases associated with hypereosinophilia and the PDGFR?(D842V) mutant in gastrointestinal stromal tumors and inflammatory fibroid polyps. To gain a better insight into the signal transduction mechanisms of PDGFR? oncogenes, we mutated twelve potentially phosphorylated tyrosine residues of FIP1L1-PDGFR? and identified three mutations that affected cell proliferation. In particular, mutation of tyrosine 720 in FIP1L1-PDGFR? or PDGFR?(D842V) inhibited cell growth and blocked ERK signaling in Ba/F3 cells. This mutation also decreased myeloproliferation in transplanted mice and the proliferation of human CD34(+) hematopoietic progenitors transduced with FIP1L1-PDGFR?. We showed that the non-receptor protein tyrosine phosphatase SHP2 bound directly to tyrosine 720 of FIP1L1-PDGFR?. SHP2 knock-down decreased proliferation of Ba/F3 cells transformed with FIP1L1-PDGFR? and PDGFR?(D842V) and affected ERK signaling, but not STAT5 phosphorylation. Remarkably, SHP2 was not essential for cell proliferation and ERK phosphorylation induced by the wild-type PDGF receptor in response to ligand stimulation, suggesting a shift in the function of SHP2 downstream of oncogenic receptors. In conclusion, our results indicate that SHP2 is required for cell transformation and ERK activation by mutant PDGF receptors.
Project description:Bronchial-pulmonary arterial fistula (BPAF) is a rare vascular malformation complicated with racemose hemangioma. We report a case of a 65-year-old male with BPAF with primary racemose hemangioma. Bronchial arteriography demonstrated convolution, dilation, and aneurysm connected with pulmonary artery, suggesting the presence of BPAF, in the left upper lobe. Since a 20-mm sized aneurysm of bronchial artery and BPAF coexisted, he underwent ligation of bronchial arterial aneurysm and left upper lobectomy to prevent hemoptysis. As neither history of prior illness nor histopathologic findings of vascular inflammation was seen, the present case demonstrated BPAF with primary racemose hemangioma. Establishment of non-invasive treatment strategy for BPAF is urgently required.
Project description:To develop traditional medicines as modern pharmacotherapies, understanding their molecular mechanisms of action can be very helpful. We have recently reported that Artemisinin and its derivatives, which are clinically used anti-malarial drugs, have significant effects against ovarian cancer, but the direct molecular targets and related combination therapy have been unclear. Herein, we report that dihydroartemisinin, one of the most active derivatives of Artemisinin, directly targets platelet-derived growth factor receptor-alpha (PDGFR?) to inhibit ovarian cancer cell growth and metastasis. Dihydroartemisinin directly binds to the intercellular domain of PDGFR?, reducing its protein stability by accelerating its ubiquitin-mediated degradation, which further inactivates downstream phosphoinositide 3-Kinase and mitogen-activated protein kinase pathways and subsequently represses epithelial-mesenchymal transition, inhibiting cell growth and metastasis of PDGFR?-positive ovarian cancer in vitro and in vivo. A combinational treatment reveals that dihydroartemisinin sensitizes ovarian cancer cells to PDGFR inhibitors. Our clinical study also finds that PDGFR? is overexpressed and positively correlated with high grade and metastasis in human ovarian cancer. Considering that Artemisinin compounds are currently clinically used drugs with favorable safety profiles, the results from this study will potentiate their use in combination with clinically used PDGFR? inhibitors, leading to maximal therapeutic efficacy with minimal adverse effects in PDGFR?-positive cancer patients. These findings also shed high light on future development of novel Artemisinin-based targeted therapy.
Project description:Kidney fibrosis is characterized by expansion and activation of platelet-derived growth factor receptor-? (PDGFR-?) positive mesenchymal cells. To study the consequences of PDGFR-ß activation, we developed a model of primary renal fibrosis using transgenic mice with PDGFR-? activation specifically in renal mesenchymal cells, driving their pathological proliferation and phenotypic switch towards myofibroblasts. This resulted in progressive mesangioproliferative glomerulonephritis, mesangial sclerosis and interstitial fibrosis with progressive anemia due to loss of erythropoietin production by fibroblasts. Fibrosis induced secondary tubular epithelial injury at later stages, coinciding with microinflammation and aggravated the progression of hypertensive and obstructive nephropathy. Inhibition of PDGFR activation reversed fibrosis more effectively in the tubulointerstitium compared to glomeruli. Gene expression signatures in mice with PDGFR-? activation resembled those found in patients. In conclusion, PDGFR-? activation alone is sufficient to induce progressive renal fibrosis and failure mimicking key aspects of chronic kidney disease in humans. Our data provide direct proof that fibrosis per se can drive chronic organ damage and establish a model of primary fibrosis allowing specific studies targeting fibrosis progression and regression.