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Retinoblastoma
Terms modified by Retinoblastoma Selected AbstractsCytopathological diagnosis of adult retinoblastoma in a vitrectomy specimen,DIAGNOSTIC CYTOPATHOLOGY, Issue 1 2010Maria E. Orellana M.D. Abstract Retinoblastoma (RB) is extremely rare in adults. We describe a case of RB diagnosed by cytology in a vitrectomy specimen of a 23-year-old patient who presented with diminished visual acuity and retinal detachment in the absence of a clinically-visible mass. Cytological examination of the vitreous fluid showed clusters of loosely cohesive atypical cells with high nuclear to cytoplasmic ratio and "salt and pepper" chromatin pattern in a background of normal neuronal retinal cells. Nuclear molding was present as well as numerous apoptotic bodies. The cells were focally positive for epithelial markers and showed strong and diffuse positivity for neuroendocrine markers. Ki-67 stained 90% of the "atypical cells" nuclei, in contrast to nonneoplastic retinal neuronal cells, which were negative for the marker. A diagnosis of RB was rendered, and subsequently was confirmed in the enucleation specimen. The cytological differential diagnosis is discussed as well as the role that cytology and immunohistochemistry can play in differentiating neoplastic cells from normal retinal cellular elements in vitreous fluid specimens. Diagn. Cytopathol. 2010. © 2009 Wiley-Liss, Inc. [source] Retinoblastoma: Review of 30 years' experience with external beam radiotherapyJOURNAL OF MEDICAL IMAGING AND RADIATION ONCOLOGY, Issue 3 2003Claire Phillips Summary A review of the experience at the Peter MacCallum Cancer Centre (Peter Mac), Melbourne, Australia in treating retinoblastoma with external beam radiotherapy was conducted. Outcomes of particular interest were tumour control, vision preservation and treatment late effects. The review was restricted to patients that had intact eyes treated at Peter Mac from 1965 until 1997 with at least 2 years of follow up. Histories were reviewed regarding patient and tumour characteristics and treatment details. Thirty-five patients were identified in whom 47 eyes were treated. Of the tumours, 47% were Reese,Ellsworth stage IV or V and the majority of others were at high risk for vision loss because of tumour location. The radiation treatment technique became increasingly sophisticated during the study period. Radiation dose and fraction size have similarly evolved but most patients received 30,50 Gy. Since 1989, a highly accurate contact lens immobilization technique has been used to deliver 40 Gy in 20 fractions. Thirteen eyes required additional local therapy. Of the treated eyes, 34 (72%) remain intact and 74% of these have useful vision. One patient died from retinoblastoma and three from second malignant neoplasms. With modern radiotherapy, late toxicities other than growth arrest and non-progressive cataract did not occur during the study period. Tumour control was high and a very acceptable rate of organ and vision preservation was achieved in a relatively high-risk population. Modern radiotherapy continues to develop in an attempt to improve treatment accuracy and minimize late radiation toxicity. [source] 1255: Diagnosis of retinoblastomaACTA OPHTHALMOLOGICA, Issue 2010L DESJARDINS Purpose Retinoblastoma is the most frequent malignant intra ocular tumors in childhood. The incidence is one out of 15000 to 18000 births. The median age at diagnosis is 24 months for unilateral and 12 months for bilateral. The genetic predisposition is autosomal do Methods In 1971 Knudson made the hypothesis that 2 genetic alterations in the same retinal cell were necessary. In bilateral disease there is one germline and one somatic mutation and in unilateral non hereditary, 2 somatic mutations. The Rb1gene is located on chromosome 13 q 1-4 . The Rb 1 protein is a pocket protein involved in the cell cycle regulation Results Most frequent symptoms are leukocoria and strabismus Later symptoms include heterochromia iridis,rubeosis, buphtalmia, pseudo hypopion, uveitis, inflammatory pseudo tumor and exophtalmia. Diagnosis of retinoblastoma is made by fundus examination. Imaging of the orbits and brain should be performed using MRI if possible. Ultrasonography with B and A scan is also useful as well as the use of Retcam . Differential diagnosis is sometimes easy when there is colobomas ,persistance of hyperplastic primary vitreous ,hamartomas or astrocytomas It can be difficult in cases of advanced Coats disease or when there is diffuse infiltrating retinoblastoma. Conclusion We have made a retrospective study on patients sent for suspicion of retinoblastoma in our institute from January 2003 to December 2005 If we compare this serie to the serie published in the literature we can say that the pourcentage of well diagnosed retinoblastoma is improving. We have found 16% of wrong diagnostics. There was 30% in the serie of Balmer in 1988 and 42% in the serie of Shields in 1991. The most frequent differential diagnosis reported in all series is Coats disease [source] 4365: The role of transpupillary thermotherapy in combined treatment of retinoblastomaACTA OPHTHALMOLOGICA, Issue 2010SV SAAKYAN Purpose Retinoblastoma (RB) is one of the most serious ophthalmic pathology in childhood. Treatment options that provide eye preservation include chemotherapy, brachytherapy, external beam radiation, cryotherapy and laser treatment. The aim of our study is to evaluate efficiency of transpupillary thermotherapy (TTT) as a part of combined treatment of RB. Methods Our group consists of 30 RB patients (34 eyes). All patients received systemic chemotherapy (Carboplatin and Vincristine). Tumor thickness before TTT varied from 0.9 to 2.6 mm, tumor base diameter varied from 2 to 10 mm. Seven patients had monolateral RB, others had bilateral lesion. Five patients were treated with brachytherapy before TTT. TTT was performed using infrared diode laser Nidec DC 3300. Exposure time was 60 seconds. Width of laser beam was from 1000 to 2000 nm. TTT power setting varied from 600 to 900 mW. Eleven patients had TTT more then once. Follow-up period after TTT was up to 24 months. Results Control examination after TTT showed good response to the treatment in 27 eyes (79.4%). After TTT we saw hyperpigmented scar on the eye fundus at the place of previous tumor location, on OCT it looked like hyper-reflective stripe replacing all layers of a retina. Seven eyes (20.6%) were resistant to TTT, five of them were successfully treated by additional brachytherapy. Two eyes were enucleated because of uncontrolled tumor growth. Evaluation of metastatic disease in all patients revealed no signs of metastasis at the time of treatment or during follow-up. Conclusion TTT can be used in combined treatment of RB for small multifocal lesions. The method is rather simple and uncomplicated. Patients treated with TTT have better visual prognosis in comparison with brachytherapy. [source] Cytopathological diagnosis of adult retinoblastoma in a vitrectomy specimen,DIAGNOSTIC CYTOPATHOLOGY, Issue 1 2010Maria E. Orellana M.D. Abstract Retinoblastoma (RB) is extremely rare in adults. We describe a case of RB diagnosed by cytology in a vitrectomy specimen of a 23-year-old patient who presented with diminished visual acuity and retinal detachment in the absence of a clinically-visible mass. Cytological examination of the vitreous fluid showed clusters of loosely cohesive atypical cells with high nuclear to cytoplasmic ratio and "salt and pepper" chromatin pattern in a background of normal neuronal retinal cells. Nuclear molding was present as well as numerous apoptotic bodies. The cells were focally positive for epithelial markers and showed strong and diffuse positivity for neuroendocrine markers. Ki-67 stained 90% of the "atypical cells" nuclei, in contrast to nonneoplastic retinal neuronal cells, which were negative for the marker. A diagnosis of RB was rendered, and subsequently was confirmed in the enucleation specimen. The cytological differential diagnosis is discussed as well as the role that cytology and immunohistochemistry can play in differentiating neoplastic cells from normal retinal cellular elements in vitreous fluid specimens. Diagn. Cytopathol. 2010. © 2009 Wiley-Liss, Inc. [source] Role of immunocytochemistry and DNA flow cytometry in the fine-needle aspiration diagnosis of malignant small round-cell tumorsDIAGNOSTIC CYTOPATHOLOGY, Issue 4 2001Urmil Brahmi M.Sc. Abstract In the present study, DNA flow cytometry (FCM) and immunocytochemistry (ICC) with a selected panel of antibodies were performed on 51 cases of malignant tumors which were referred for fine-needle aspiration biopsy (FNAB) to our Department of Cytology for the last 2 yr. Twelve cases were diagnosed as neuroblastoma, 16 as Ewing's sarcoma, 2 as retinoblastoma, 5 as non-Hodgkin's lymphoma (NHL), 5 as rhabdomyosarcoma, 2 as peripheral neuroectodermal tumors (PNETs), and 8 as Wilms' tumor. Eleven of 12 neuroblastomas were diploid by FCM, and 1 was aneuploid, with an S-phase fraction (SPF) of 8.3%. Neuron-specific enolase (NSE) was negative in 3 and positive in 8 cases of neuroblastoma, whereas neuroblastoma marker was positive in 3/11. Sixteen of 17 Ewing's sarcomas were diploid, and 1 showed tetraploid aneuploidy, with an SPF of 10.06%. Eight of 13 Ewing's sarcomas were positive for Mic-2 gene product (Ewing's marker). All 5 NHL were positive for leukocyte-common antigen (LCA). Three of 5 rhabdomyosarcomas were diploid, and 2 cases showed aneuploidy. Rhabdomyosarcoma showed muscle-specific actin positivity in 4 and desmin positivity in 3 cases. All 3 cases of PNET were diploid and positive for the Mic-2 gene product, whereas NSE and vimentin were positive in 2 cases. Both cases of retinoblastoma were diploid. Immunostaining was noncontributory in 1 case, and the other showed positivity for the retinoblastoma gene product, NSE, and chromogranin. Seven of 8 Wilms' tumors were diploid, and 1 showed aneuploid, with an SPF of 11.13%. Seven of 8 Wilms' tumors were positive for cytokeratin (CK), 5 were positive for NSE, 6 were positive for epithelial membrane antigen (EMA), and 5 were positive for vimentin. FNAB diagnosis of malignant round-cell tumors is difficult only by light microscopy. Due to the availability of specific markers for subgrouping tumors, ICC has proved to be more useful these days, while DNA FCM has little diagnostic value, as most of them are diploid. Further ancillary studies, e.g., electron microscopy, image analysis, and other molecular investigations, are required to further categorize these tumors more precisely for better clinical management of these cases. Diagn. Cytopathol. 24:233,239, 2001. © 2001 Wiley-Liss, Inc. [source] Profiling genomic copy number changes in retinoblastoma beyond loss of RB1GENES, CHROMOSOMES AND CANCER, Issue 2 2007Ella Bowles Loss of both RB1 alleles is rate limiting for development of retinoblastoma (RB), but genomic copy number gain or loss may impact oncogene(s) and tumor suppressor genes, facilitating tumor progression. We used quantitative multiplex polymerase chain reaction to profile "hot spot" genomic copy number changes for gain at 1q32.1, 6p22, and MYCN, and loss at 16q22 in 87 primary RB and 7 cell lines. Loss at 16q22 (48%) negatively associated with MYCN gain (18%) (Fisher's exact P = 0.031), gain at 1q32.1 (62%) positively associated with 6p "hot spot" gain (43%) (P = 0.033), and there was a trend for positive association between 1q and MYCN gain (P = 0.095). Cell lines had a higher frequency of MYCN amplification than primary tumors (29% versus 3%; P= 0.043). Novel high-level amplification of 1q32.1 in one primary tumor, confirmed by fluorescence in situ hybridization, strongly supports the presence of oncogene(s) in this region, possibly the mitotic kinesin, KIF14. Gene-specific quantitative multiplex polymerase chain reaction of candidate oncogenes at 1q32.1 (KIF14), 6p22 (E2F3 and DEK), and tumor suppressor genes at 16q22 (CDH11) and 17q21 (NGFR) showed the most common gene gains in RB to be KIF14 in cell lines (80%) and E2F3 in primary tumors (70%). The patterns of gain/loss were qualitatively different in 25 RB compared with 12 primary hepatocellular carcinoma and 12 breast cancer cell lines. Gene specific analysis of one bone marrow metastasis of RB, prechemotherapy and postchemotherapy, showed the typical genomic changes of RB pretreatment, which normalized after chemotherapy. © 2006 Wiley-Liss, Inc. [source] The expression of key cell cycle markers and presence of human papillomavirus in squamous cell carcinoma of the tonsilHEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 1 2004Wei Li MMed Abstract Background. Chemical carcinogens induce squamous cell carcinoma (SCC) of the head and neck by targeting the p53 and the retinoblastoma (pRb) pathways. Human papillomavirus (HPV) might have an etiologic role in these cancers at particular sites. Few studies have compared cell cycle protein expression in HPV-positive and HPV-negative tumors in this region. Methods. Fifty tonsil SCCs were analyzed for HPV by PCR and for expression of cell cycle proteins (p53, pRb, p16INK4A, p21CIP1/WAF1, p27KIP1, and cyclinD1) by immunohistochemistry. Results. HPV was present in 42%; almost all were type 16. There were statistical associations between HPV positivity and reduced expression of pRb and cyclinD1, overexpression of p16, and younger patient age. Tumor with down-regulated p27 tended to have down-regulated pRb and p21. Conclusions. HPV-positive tonsil SCCs have distinct molecular pathways. Their association with younger patient age suggests that they are biologically distinct from HPV-negative tumors. © 2004 Wiley Periodicals, Inc. Head and Neck 26: 1,9, 2004 [source] Genomic and immunophenotypical differences between hepatocellular carcinoma with and without cirrhosisHISTOPATHOLOGY, Issue 6 2010Maria S Tretiakova Tretiakova M S, Shabani-Rad M T, Guggisberg K, Hart J, Anders R A & Gao Z-h (2010) Histopathology,56, 683,693 Genomic and immunophenotypical differences between hepatocellular carcinoma with and without cirrhosis Aims:, To compare the expression of genes involved in p53, Wnt/,-catenin, and retinoblastoma (Rb) 1 pathways between cirrhosis-associated hepatocellular carcinoma (HCC-C) and hepatocellular carcinoma arising in non-cirrhotic liver (HCC-NC). Methods and results:, The gene expression profile was analysed using oligo-DNA arrays, and then validated at protein level in a tissue microarray using immunohistochemistry. Compared with their background non-neoplastic liver tissue, HCC-C showed a significantly higher rate of p53, ,-catenin (protein only) and cyclin D1 expression, whereas HCC-NC showed a significantly higher rate of p21Waf1/cip1 and p27Kip1 expression. HCC-C had a significantly higher rate of p53 expression and a significantly lower rate of p21waf1/cip1 expression than HCC-NC. There was no statistically significant association between the expression of genetic markers and tumour histological grade, underlying aetiology, or lymphovascular invasion. Aberrant ,-catenin expression was more commonly seen in single tumours in comparison with multiple tumours. Increased p16INK4 and p21waf1/cip1 expression was more commonly observed in large-sized tumours (>50 mm) than small-sized tumours. Conclusions:, Alteration of the p53 pathway plays a more important role in the pathogenesis of HCC-C, whereas alterations in cell cycle regulators p21waf1/cip1 and p27Kip1 play a more important role in the pathogenesis of HCC-NC. [source] Genotype,phenotype correlations in hereditary familial retinoblastoma,HUMAN MUTATION, Issue 3 2007Melissa Taylor Abstract We studied 50 unrelated pedigrees with a family history of retinoblastoma (Rb) (165 carriers of a RB1 mutation) to delineate the spectrum of RB1 germline mutations in familial Rb and to identify genotype,phenotype correlations as well as putative modifiers. Patients were followed at Institut Curie and they were examined by an ophthalmologist, a pediatrician, and a geneticist. All cases of familial Rb were determined via genetic counseling. Clinical features included disease status, laterality, age at diagnosis, mutation type, follow-up, and disease,eye ratio (DER). To eliminate mosaic cases, first-generation carriers displaying low-penetrance (LP) Rb were excluded from the analysis. Complete penetrance was the rule for nonsense and frameshift mutations (25 families) and high penetrance was observed for large rearrangements (eight families). Promoter (two families) and missense (two families) mutations displayed heterogeneous phenotypes and LP. Variable penetrance was observed for splice abnormalities (13 families) and was explained by in/out of frame mutations or respect of functional domains. Surprisingly, two families with the LP g.45867G>T/IVS6+1G>T mutation presented data that conflicted with the data reported in previous publications, as unaffected carriers had paternally inherited mutant alleles. Moreover, RNA analyses suggested that the lack of penetrance in unaffected carriers could be explained by an increase in expression levels of the wild-type allele. This observation prompted us to define a new class "3" of LP alleles. We believe this is the first large-scale study of familial Rb with a high level of homogeneity in the clinical and genetic analysis of patients and their relatives, thereby allowing for reliable intrafamilial genotype,phenotype correlations. Our analysis suggests in some cases the influence of modifier factors probably involved in mRNA level regulation and/or pRB pathway regulation. Hum Mutat 28(3), 284,293, 2007. © 2006 Wiley-Liss, Inc. [source] Annexin-A7 protects normal prostate cells and induces distinct patterns of RB-associated cytotoxicity in androgen-sensitive and -resistant prostate cancer cells,INTERNATIONAL JOURNAL OF CANCER, Issue 11 2009Yelizaveta Torosyan Abstract The tumor suppressor role of annexin-A7 (ANXA7) was previously demonstrated by cancer susceptibility in Anxa7(+/,)-mice and by ANXA7 loss in human cancers, especially in hormone-resistant prostate tumors. To gain mechanistic insights into ANXA7 tumor suppression, we undertook an in vitro study in which we compared wild-type (WT)-ANXA7 and dominant-negative (DN)-ANXA7 effects to a conventional tumor suppressor p53 in prostate cancer cells with different androgen sensitivity. Unlike p53 (which caused cell growth arrest and apoptosis to a noticeable extent in benign PrEC), WT-ANXA7 demonstrated profound cytotoxicityin androgen-sensitive LNCaP as well as in the androgen-resistant DU145 and PC3 prostate cancer cells, but not in PrEC. In androgen-sensitive LNCaP, WT-ANXA7 decreased low-molecular-weight (LMW) AR protein forms and maintained higher retinoblastoma 1 (RB1)/phospho-RB1 ratio. In contrast, DN-ANXA7 (which lacks phosphatidylserine liposome aggregation properties) increased LMW-AR forms and hyperphosphorylated RB1 that was consistent with the lack of DN-ANXA7 cytotoxicity. According to the microarray-based Ingenuity Pathways Analysis, a major WT-ANXA7 effect in androgen-sensitive LNCaP constituted of upregulation of the RB1-binding transcription factor E2F1 along with its downstream proapoptotic targets such as ASK1 and ASPP2. These results suggested a reversal of the RBdependent repression of the proapoptotic E2F-mediated transcription. However, DN-ANXA7 increased RB1/2 (but not E2F1) expression and induced the proliferation-promoting ERK5, thereby maintaining the RB-dependent repression of E2F-mediated apoptosis in LNcaP. On the other hand, in androgen-resistant cells, WT-ANXA7 tumor suppressor effects involved PTEN and NFkB pathways. Thus, ANXA7 revived the RB-associated cell survival control and overcame androgen resistance and dysfunctional status of major tumor suppressors commonly mutated in prostate cancer. Published 2009 UICC. [source] The p75NTR neurotrophin receptor is a tumor suppressor in human and murine retinoblastoma developmentINTERNATIONAL JOURNAL OF CANCER, Issue 9 2008Helen Dimaras Abstract The transition from the benign retinal tumor retinoma to its malignant counterpart retinoblastoma is accompanied by the loss of expression of the p75NTR neurotrophin receptor. This change in expression is mimicked in the TAg-RB murine model of retinoblastoma, where early tumors retain expression of p75NTR and advanced tumors lack it. We sought to determine the functional effect on tumor development of absence of p75NTR from the onset of TAg-RB tumor initiation. TAg-RB mice were crossed with either p75NTR exon 3 (E3KO) or exon 4 knockout (E4KO) mice to produce TAg-RB offspring that lacked one or both normal p75NTR alleles. The average tumor area per eye as a percentage of retinal area was measured. TAg-RB/E3KO (TAg-RBE3KO) and heterozygous mice showed no significant difference in tumor area compared to the TAg-RB control mice at any time point studied. However, TAg-RB/E4KO (TAg-RBE4KO) and heterozygous mice displayed a significantly larger tumor area than the TAg-RB control mice. Furthermore, adenoviral-mediated expression of p75NTR in a p75NTR -deficient human retinoblastoma cell line resulted in increased apoptosis. Our results confirm that p75NTR suppresses progression of both human and TAg-RB murine retinoblastoma, and holds promise as a target for future therapy of the disease. © 2008 Wiley-Liss, Inc. [source] On the dynamics of breast tumor development in women carrying germline BRCA1 and BRCA2 mutationsINTERNATIONAL JOURNAL OF CANCER, Issue 8 2008Richard Simon Abstract We used mathematical models to analyze the age-incidence curve of breast carcinoma for individuals carrying a germline mutation in the BRCA1 or BRCA2 gene locus. Although many genomic abnormalities have been identified in breast tumors, we found that a two-stage model fit the data well. A one-hit model was not, however, consistent with the data. The results supported the hypothesis that the first hit represents loss of the wild type BRCA1 or BRCA2 allele as this occurs at a rate very similar to that for loss of the wild-type RB allele in retinoblastoma. Loss of the wild-type BRCA1 or BRCA2 allele appears to destabilize the genome as the second event occurs at a much higher rate. The second event is "rate limiting" in the sense that its occurrence is constrained by the limited number of intermediate cells with doubly mutated BRCA1 or BRCA2 alleles. The second event may not be unique, however. Loss of the wild-type BRCA allele appears to result in an increased rate for subsequent genomic events. A second event increasing proliferation of the partially malignant intermediate clone may lead inexorably to production and selection of cells with additional mutations in genes that facilitate tumor progression. © 2007 Wiley-Liss, Inc. [source] New malignancies following childhood cancer in the United States, 1973,2002INTERNATIONAL JOURNAL OF CANCER, Issue 10 2007Peter D. Inskip Abstract The objectives of our study were to quantify risks for developing new malignancies among childhood cancer survivors, identify links between particular types of first and subsequent cancer, and evaluate the possible role of treatment. A cohort of 25,965 2-month survivors of childhood cancer diagnosed in the U.S. during 1973,2002 was identified and followed through SEER cancer registries. Observed-to-expected ratios (O/E) were calculated, and Poisson regression was used to compare risks among treatment groups. Childhood cancer survivors were at nearly 6-fold risk of developing a new cancer relative to the general population (O/E = 5.9, 95% CI: 5.4,6.5). Most common were subsequent primary cancers of the female breast, central nervous system, bone, thyroid gland and soft tissue, as well as cutaneous melanoma and acute non-lymphocytic leukemia (ANLL). The greatest risks of subsequent cancers occurred among patients diagnosed previously with Hodgkin lymphoma (HL), Ewing sarcoma, primitive neuroectodermal tumor, or retinoblastoma. Risk of subsequent solid cancers was higher among persons whose initial treatment for childhood cancer included radiotherapy, whereas the excess of subsequent ANLL was strongly related to chemotherapy. The O/E for subsequent ANLL increased with increasing calendar year of initial cancer diagnosis among survivors of cancers other than HL, most likely due to increasing use of leukemogenic drugs for solid cancers and non-Hodgkin lymphoma. Childhood cancer survivors are at markedly increased risk of developing a variety of new cancers relative to the general population, but the magnitude of excess risk and specific types of second cancer vary widely by type of first cancer. © 2007 Wiley-Liss, Inc. [source] Changes in retinoblastoma gene expression during cervical cancer progressionINTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY, Issue 6 2002Mauricio Salcedo Summary. The role of tumour suppressor genes in the development of human cancers has been studied extensively. In viral carcinogenesis, the inactivation of suppressor proteins such as retinoblastoma (pRb) and p53, and cellular oncogenes overexpression, such as c-myc, has been the subject of a number of investigations. In uterine-cervix carcinomas, where high-risk human papillomavirus (HPV) plays an important role, pRb and p53 are inactivated by E7 and E6 viral oncoproteins, respectively. However, little is known about the in situ expression of some of these proteins in pre-malignant and malignant cervical tissues. On the other hand, it has also been demonstrated that c-myc is involved in cervical carcinogenesis, and that pRb participates in the control of c-myc gene expression. By using immunostaining techniques, we investigated pRb immunodetection pattern in normal tissues, squamous intraepithelial lesions (SILs) and invasive carcinomas from the uterine cervix. Our data show low pRb detection in both normal cervical tissue and invasive lesions, but a higher expression in SILs. C-Myc protein was observed in most of the cellular nuclei of the invasive lesions, while in SILs was low. These findings indicate a heterogeneous pRb immunostaining during the different stages of cervical carcinogenesis, and suggest that this staining pattern could be a common feature implicated in the pathogenesis of uterine-cervix carcinoma. [source] Molecular aspects of diagnostic nucleolar and nuclear envelope changes in prostate cancerJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 1 2004Andrew H. Fischer Abstract Prostate cancer is still diagnosed by pathologists based on subjective assessment of altered cell and tissue structure. The cellular-level structural changes diagnostic of some forms of cancer are known to be induced by cancer genes, but the relation between specific cellular-level structural features and cancer genes has not been explored in the prostate. Two important cell structural changes in prostate cancer,nucleolar enlargement and nuclear envelope (NE) irregularity,are discussed from the perspective that they should also relate to the function of the genes active in prostate cancer. Enlargement of the nucleolus is the key diagnostic feature of high-grade prostatic intraepithelial neoplasia (PIN), an early stage that appears to be the precursor to the majority of invasive prostate cancers. Nucleolar enlargement classically is associated with increased ribosome production, and production of new ribosomes appears essential for cell-cycle progression. Several cancer genes implicated in PIN are known (in other cell types) to augment ribosome production, including c-Myc, p27, retinoblastoma, p53, and growth factors that impact on ERK signaling. However, critical review of the available information suggests that increased ribosome production per se may be insufficient to explain nucleolar enlargement in PIN, and other newer functions of nucleoli may therefore need to be invoked. NE irregularity develops later in the clonal evolution of some prostate cancers, and it has adverse prognostic significance. Nuclear irregularity has recently been shown to develop dynamically during interphase following oncogene expression, without a requirement for post-mitotic NE reassembly. NE irregularity characteristic of some aggressive prostate cancers could reflect cytoskeletal forces exerted on the NE during active cell locomotion. NE irregularity could also promote chromosomal instability because it leads to chromosomal asymmetry in metaphase. Finally, NE irregularity could impact replication competence, transcriptional programming and nuclear pore function. © 2003 Wiley-Liss, Inc. [source] Sequential loss of cell cycle checkpoint control contributes to malignant transformation of murine embryonic fibroblasts induced by 20-methylcholanthreneJOURNAL OF CELLULAR PHYSIOLOGY, Issue 1 2010Sudeshna Mukherjee Definitive information about the number and nature of discrete steps of tumorigenesis is enigmatic. To understand the multistep nature of carcinogenesis, an in vitro model of 20-Methylcholanthrene-treated primary fibroblast cells CNCI-PM-20, from 20-day old Swiss mouse embryo was used. Visible neoplastic changes with distinct morphological variations along with specific chromosomal aberrations like Robertsonian metacentrics, double and single-minute chromosomes and aneuploidy were observed from Passage-20 onwards. The cell cycle profile showed gradual increase in G2/M population till P-32, followed by evasion of block from P-36 onwards. Gradual increase in expression of C-myc, CyclinD1 and a decrease in expression of P21 was observed from P-20 onwards. CDC25A expression was significantly increased at P-27 and remained more or less constant in subsequent passages. Additionally, an increased P16 and P53 expression were seen at P-20 followed by their significant down-regulation at P-32. An increased level of phosphorylated retinoblastoma (ppRb) was observed from P-27, probably responsible for a compromised G1/S checkpoint. The inactivation of p21 and p16 might be due to their promoter hyper-methylation as suggested through de-methylation experiment by 5-aza-deoxycytidine at P-42. G2/M checkpoint abrogation was marked by gradual increase in expression of CyclinB1 and Cdc20, and a significant increase of Mad2 at P-20. Interestingly, increased expression of phospho-ATM, ATR and phospho-Chk1 were also seen at P-20 followed by their down-regulation at subsequent passages, indicating a perturbation of DNA damage response pathway at early passages. Our findings therefore dramatize the multiple genetic events that can cooperate to promote tumorigenesis. J. Cell. Physiol. 224:49,58, 2010 © 2010 Wiley-Liss, Inc. [source] Bone-specific heparan sulfates induce osteoblast growth arrest and downregulation of retinoblastoma proteinJOURNAL OF CELLULAR PHYSIOLOGY, Issue 1 2006Kerry J. Manton The heparan sulfate (HSs) sugars of the extracellular matrix (ECM) play a key role during both development and wound repair in regulating the flow of growth and adhesive factors across their cell surface receptors. The aim of this study was to assess the structural and functional differences of HS chains extracted from the conditioned media (soluble), cell surface, and ECM of primary human osteoblast cultures, and to analyze their effects on osteoblast cell growth. HS chains from these compartments were characterized through a combination of enzymatic degradation, anion exchange chromatography, and molecular sieving. Although the chains were all approximately the same size, they varied systematically in their sulfate content, suggesting differences in their protein-binding domains. When added to pre-confluent hFOB1.19 osteoblast cultures, HS doses exceeding 500 ng/ml inhibited proliferation, without affecting viability, irrespective of their origin. Furthermore, HS doses of 500 ng/ml also downregulated retinoblastoma, Cyclin A and CDK1 protein expression, indicating that high doses of osteoblast HS negatively regulate cell cycle, resulting in growth arrest; when high doses of HS were withdrawn after a prolonged period, linear cell growth was reestablished. Thus, despite differences in sulfation, HS from either the soluble, cell surface, or matrix compartments of primary human osteoblast cultures are functionally similar with respect to their effects on growth. Binding assays revealed that the HS chains bound TGF,1, a known inhibitor of osteoprogenitor growth, at higher affinity than a suite of other bone-related, heparin-binding growth factors. Overcoming such sugar-mediated inhibition may prove important for wound repair. J. Cell. Physiol. 209: 219,229, 2006. © 2006 Wiley-Liss, Inc. [source] Retinoblastoma gene expression in human non-melanoma skin cancerJOURNAL OF CUTANEOUS PATHOLOGY, Issue 8 2003Malcolm J. Edwards Background:, The aberrant expression of both the retinoblastoma and p53 tumor suppressor genes has been associated with more aggressive tumors, metastasis and lower survival. Methods:, We have evaluated immunohistochemically the expression of pRB in a panel of non-melanoma skin cancers containing p53 somatic mutations. Results:, Nuclear anti-p53 staining was detected in 18 (72%) differentiated squamous cell carcinomas, six (100%) undifferentiated squamous cell carcinomas and seven (28%) basal cell carcinomas. A correlation was observed between p53 expression and the proliferative activity of differentiated squamous cell carcinomas (P < 0.066), undifferentiated squamous cell carcinomas (P < 0.05) and basal cell carcinomas (P < 0.01). Tumors were selected for mutant p53 expression by PCR-directed DNA sequencing and pRB expression measured immunohistochemically. Anti-pRB reactivity was detected in the nuclei of basal and suprabasal layer cells of normal epidermis, and in the proliferative compartment of all the differentiated squamous cell carcinomas, and basal cell carcinomas. A correlation was observed between pRB expression and the proliferative activity of the differentiated squamous cell carcinomas (P < 0.01) and basal cell carcinomas (P < 0.025). However, anti-pRB reactivity was not detected in the six anti-p53 reactive undifferentiated squamous cell carcinomas. [source] Involvement of the INK4a/Arf gene locus in senescenceAGING CELL, Issue 3 2003Carol J. Collins Summary The INK4a/ARF locus encodes two proteins whose expression limits cellular proliferation. Whilst the biochemical activities of the two proteins appear very different, they both converge on regulating the retinoblastoma and p53 tumour suppressor pathways. Neither protein is required for normal development, but lack of either predisposes to the development of malignancy. Both proteins have also been implicated in the establishment of senescence states in response to a variety of stresses, signalling imbalances and telomere shortening. The INK4a/Arf regulatory circuits appear to be partially redundant and show evidence of rapid evolution. Especially intriguing are the large number of biological differences documented between mice and man. We review here the brief history of INK4a/Arf and explore possible links with organismal aging and the evolution of longevity. [source] Retinoblastoma: Review of 30 years' experience with external beam radiotherapyJOURNAL OF MEDICAL IMAGING AND RADIATION ONCOLOGY, Issue 3 2003Claire Phillips Summary A review of the experience at the Peter MacCallum Cancer Centre (Peter Mac), Melbourne, Australia in treating retinoblastoma with external beam radiotherapy was conducted. Outcomes of particular interest were tumour control, vision preservation and treatment late effects. The review was restricted to patients that had intact eyes treated at Peter Mac from 1965 until 1997 with at least 2 years of follow up. Histories were reviewed regarding patient and tumour characteristics and treatment details. Thirty-five patients were identified in whom 47 eyes were treated. Of the tumours, 47% were Reese,Ellsworth stage IV or V and the majority of others were at high risk for vision loss because of tumour location. The radiation treatment technique became increasingly sophisticated during the study period. Radiation dose and fraction size have similarly evolved but most patients received 30,50 Gy. Since 1989, a highly accurate contact lens immobilization technique has been used to deliver 40 Gy in 20 fractions. Thirteen eyes required additional local therapy. Of the treated eyes, 34 (72%) remain intact and 74% of these have useful vision. One patient died from retinoblastoma and three from second malignant neoplasms. With modern radiotherapy, late toxicities other than growth arrest and non-progressive cataract did not occur during the study period. Tumour control was high and a very acceptable rate of organ and vision preservation was achieved in a relatively high-risk population. Modern radiotherapy continues to develop in an attempt to improve treatment accuracy and minimize late radiation toxicity. [source] Abnormal Expression of p16INK4a, Cyclin D1, Cyclin-Dependent Kinase 4 and Retinoblastoma Protein in Gastric Carcinomas,JOURNAL OF SURGICAL ONCOLOGY, Issue 1 2008Ichiro Kishimoto MD Abstract Background and Objectives The p16INK4a (p16), cyclin D1, cyclin-dependent kinase (CDK) 4 and retinoblastoma (Rb) genes are components of the Rb pathway that controls the G1-S checkpoint of the cell cycle. The aim of this study was to assess the relationship between their abnormalities and clinicopathological features in gastric carcinomas. Mehtods Immunohistochemical analysis of the encoded proteins was performed on a series of 158 cases. Results Loss of p16/Rb protein (pRb) expression and overexpression of cyclin D1/CDK4 were observed in 49%/40% and 37%/37% of gastric carcinomas, respectively. At least 1 of these abnormalities was found in 86% of the cases and a positive correlation was noted between p16 and pRb (P,=,0.009). Cyclin D1 (P,=,0.042) and CDK4 (P,=,0.008) overexpession was inversely associated with lymph node metastasis and depth of invasion, respectively. Loss of pRb expression was more frequently in diffuse type lesions than in the intestinal type (P,=,0.022). The patients with p16+/pRb,/cyclin D1,/CDK4, or p16,/pRb+/cyclin D1,/CDK4, tumors demonstrated particularly poor survival. With multivariate survival analysis, only depth of invasion and TNM stage could be proven as independent predictors. Conclusions The Rb pathway is disrupted in the vast majority of gastric carcinomas. This study also identified specific immunohistochemical marker profiles for prognosis. J. Surg. Oncol. 2008;98:60,66. © 2008 Wiley-Liss, Inc. [source] The role of p28GANK in rat oval cells activation and proliferationLIVER INTERNATIONAL, Issue 2 2006Yun-Feng Shan Abstract: Background: Human gankyrin gene product (p28GANK) is a novel oncogenic protein ubiquitously overexpressed in hepatocellular carcinoma and also plays a role in cell cycle progression in normal hepatocytes and liver regeneration. However, little is known about the physiological role of p28GANK in the liver oval cell activation and proliferation. We investigated the possible involvement of p28GANK in oval cell-mediated liver regeneration and cell cycle progression. Methods: We examined the different p28GANK expression in 2-acetylaminofuorene/partial heptectomy (2-AAF/PH) rats, as a model of oval cell activation, and PH rats by Western blot and immunohistochemistry. Oval cells isolated from 2-AAF/PH rat model were cultured in our study. p28GANK expression was examined in the oval cells after mitogenic stimulation. Results: In 2-AAF/PH rats, p28GANK was expressed in the activated oval cells and located in the nucleus. p28GANK protein expression was increased in 2-AFF/PH rats after hepatectomy lasting for 96 h when retinoblastoma maintained hyperphosphorylation status at Ser-795. The isolated oval cells express AFP, OV6, CK19, CD34, CD45, c-kit and albumin. After epidermal growth factor stimulation, p28GANK protein was up-regulated in oval cells from 24 to 72 h, which coincided with increased expression of CyclinD1, CDK4 and decreased of Rb protein. Conclusions: p28GANK expression was increased in oval cell-mediated liver regeneration and oval cells after mitogenic stimulation. Thus, p28GANK may play a role in oval cell-mediated liver regeneration and liver oval cell cycle progression. [source] Pinealoblastoma with prominent retinoblastic differentiation: An unusual case in an adultNEUROPATHOLOGY, Issue 4 2010Nandita Ghosal We present an extremely rare case of pinealoblastoma with retinoblastic differentiation in a 32-year-old woman who presented with a history of intermittent headache of 2 years duration and diminution of vision for 2 months which eventually lead to total loss of vision. The fundus examination showed bilateral secondary optic atrophy. She did not have any previous history of retinoblastoma. The family history was non-contributory. Paraffin section of the tumor showed a primitive neuroectodermal tumor with numerous Flexner-Wintersteiner rosettes and the tumor cells were strongly positive for synaptophysin and negative for GFAP, S-100 protein and epithelial membrane antigen. This is the first case in the literature of a sporadic case of pinealoblastoma with prominent retinoblastic differentiation as evidenced histomorphologically by the presence of numerous Flexner-Wintersteiner rosettes in an adult female. [source] Phosphorylation of retinoblastoma protein in rat brain after transient middle cerebral artery occlusionNEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 4 2000T. Hayashi Although mature neurones do not replicate genomic DNA, some cell cycle-related kinases are aberrantly activated in neurones after ischaemia. As hyper-phosphorylation of retinoblastoma (Rb) protein is the common pathway in mitotic signal cascade, this study investigated the phosphorylation state of the Rb protein as well as its mRNA level in rat brain after transient middle cerebral artery (MCA) occlusion. Immunohisto-chemical analysis revealed that neurones in the sham-operated brain expressed Rb protein without the hyperphosphorylated form. Immunoreactivity for the hyperphosphorylated form of Rb protein progressively increased from 1 h to 3 days after ischaemia in neurones in the MCA territory. Western blot analysis demonstrated a similar change. However, reverse transcription-polymerase chain reaction study revealed that Rb showed no definite change at the mRNA level. These results suggest that Rb protein is progressively hyper-phosphorylated in the brain after ischaemia, which may activate apoptotic mechanisms in neuronal cells of the brain after ischaemia. [source] Epidemiological characteristics of retinoblastoma in children attending the Mexican Social Security Institute in Mexico City, 1990,94PAEDIATRIC & PERINATAL EPIDEMIOLOGY, Issue 4 2002Víctor Amozorrutia-Alegría Summary The object of this study is to present descriptive epidemiological characteristics of retinoblastoma (Rb) in children aged 0,14 years, seen at the Mexican Social Security Institute hospitals in Mexico City (MC) from 1990 to 1994. This is a retrospective, observational hospital survey. Clinical records of 52 Rb cases were reviewed; 39 were patients who did not reside in MC (non-residents), and 13 were MC residents. The study period was 1990,94. The male/female ratio (M/F) was 1.6. Average annual incidence (AAI) was estimated by age and sex (rates per 1 000 000). Annual average percentage change (AAPC) in incidence rates was estimated in children from 0 to 14 years. The AAI for MC residents was 3.2; the highest rate being for those <1 year olds (rate of 20.8); AAPC was 6.9% [95% CI ,27.5, 57.4]; the highest incidence was for the south-eastern region of MC residents (rate of 5.9); 13 cases (25%) were diagnosed at stage III or IV, and 11 cases (21.2%) were bilateral. Incidence of Rb is similar to that in developed countries and shows no increasing trend. Patients from communities outside MC are more frequently diagnosed at stages III and IV. [source] An interim analysis of a cohort study on the preoperative anxiety and postoperative behavioural changes in children having repeat anaestheticsPEDIATRIC ANESTHESIA, Issue 9 2002A. Watson Introduction Anxiety in the preoperative period and at induction of anaesthesia in children is associated with disturbances in postoperative behaviour (1,4). There is little work looking at the effects of repeat anaesthetic procedures on anxiety and subsequent postoperative behaviour disturbances. The aim of this study was to see if the effect of repeat anaesthetics was cumulative on postoperative behavioural problems and whether repeated anaesthetics provoke increasing anxiety. We investigated factors that may identify children who are susceptible to behavioural changes following repeat anaesthetics. We present an interim analysis of data on 8 patients as part of a long-term cohort study on 40 children with retinoblastoma who have required repeat anaesthetics for assessment and treatment of their condition. Method Approval for this study was granted by the East London and City Health Authority ethics committee. 40 patients are being recruited and being followed over a two year period. All children have retinoblastoma and are between the ages of 18 months to 4 years. The anaesthetic technique was not standardised but details of it were collected. Data collected were demographic details of child (age, sex, weight, ASA grade, siblings, stressful events in the last 3 months, recent immunisations, number of previous anaesthetics, problems with previous general anaesthetics, medical history of children, temperament of child using the EASI scoring system (4); demographic data of parents (age, parental education, family members affected, baseline measure of parental anxiety using State trait anxiety inventory (STAI). Anxiety on entry into the anaesthetic room and at induction was measured by the modified Yale preoperative anxiety scale (mYPAS), cooperation of the child at induction was measured by the Induction compliance checklist (ICC). Anxiety of the parent after induction was measured by the STAI score. Behaviour was measured at 1 day, 1 week, 1 month and 4 months after each procedure by means of the post hospital behaviour score (PHBQ) (5). A comparison with preoperative behaviour was made and data is presented of the percentage of children with new negative behavioural problems. A detailed analysis of the types of behaviour change was noted. anova for repeat measures with multiple dependent measures was used to analyse data on child anxiety and postoperative behavioural problems. Results Eight patients have had 3 separate anaesthetics over one and a half years. These have been at 4 monthly intervals. There was no significant increase in anxiety levels with repeat anaesthetics. The median mYPAS score at induction were 100 for all 3 anaesthetics. (P = 0.41). The type of behavioural change was variable and demonstrated no trend. No patient was identified as being prone to behavioural changes after every anaesthetic. Patients who displayed new negative behavioural problems would have them after any anaesthetic with no obvious cumulative effect with each repeat anaesthetic. Conclusions Our patients had maximum anxiety scores at induction, so the mYPAS scoring system is not sensitive enough to show that repeat anaesthetics provoke increasing anxiety. There is a very random pattern to behavioural disturbances after repeat anaesthetics with no evidence that negative behavioural changes are compounded with repeated anaesthetics. Collection of complete data from the remaining 32 patients may yield some trends regarding behavioural disturbances but our use of the mYPAS to measure anxiety in this very anxious population is unlikely to be helpful. [source] Successful treatment of early detected trilateral retinoblastoma using standard infant brain tumor therapy,PEDIATRIC BLOOD & CANCER, Issue 3 2010Karen D. Wright MD Abstract Trilateral retinoblastoma is characterized by the presence of retinoblastoma with an intracranial tumor. The incidence is low and prognosis poor. Due to the paucity of information regarding successful treatment, we report the case of a 6 month old female referred for leukocoria and found to have an associated suprasellar tumor and pineal enhancement. The patient, treated with standard infant brain tumor therapy, remains alive without signs of active disease 35 months after diagnosis; no surgery or irradiation was used. Early diagnosis of trilateral retinoblastoma may facilitate the use of less intensive therapeutic approaches and result in excellent outcomes in these patients. Pediatr Blood Cancer. 2010;55:570,572. © 2010 Wiley-Liss, Inc. [source] High-dose chemotherapy with autologous hematopoietic stem cell rescue for stage 4B retinoblastoma,PEDIATRIC BLOOD & CANCER, Issue 1 2010Ira J. Dunkel MD Abstract Background Stage 4b retinoblastoma (central nervous system metastatic disease) has been lethal in virtually all cases reported. Here we describe a series of eight patients treated with intensive chemotherapy, defined as the intention to include high-dose chemotherapy with autologous hematopoietic stem cell rescue. Procedure Induction chemotherapy included cyclophosphamide and/or carboplatin with a topoisomerase inhibitor. High-dose chemotherapy regimens were carboplatin and thiotepa with or without etoposide (n,=,3) or carboplatin, etoposide, and cyclophosphamide (n,=,2). Results Seven patients had leptomeningeal disease and one patient had only direct extension to the CNS via the optic nerve. Three patients had stage 4b disease at the time of original diagnosis of the intra-ocular retinoblastoma; five had later onset at a median of 12 months (range 3,69 months). One patient died of toxicity (septicemia and multi-organ system failure) during induction and two had disease progression prior to high-dose chemotherapy. Five patients received high-dose chemotherapy at a median of 6 months (range 4,6) post-diagnosis of stage 4b disease. Two patients survive event-free at 40 and 101 months; one was irradiated following recovery from the high-dose chemotherapy. Conclusions Intensive multimodality therapy may be beneficial for some patients with stage 4b retinoblastoma. Longer follow-up will determine whether it has been curative. Pediatr Blood Cancer 2010;55:149,152. © 2010 Wiley-Liss, Inc. [source] Monitoring of ototoxicity in young children receiving carboplatin for retinoblastomaPEDIATRIC BLOOD & CANCER, Issue 6 2009Mathilde Jehanne MD No abstract is available for this article. [source] | ||||||||||||||||||||||||||||||||||