Current Issue : April - June Volume : 2012 Issue Number : 2 Articles : 6 Articles
Background: The study of breast cancer metastasis depends on the use of established breast cancer cell lines that\r\ndo not accurately represent the heterogeneity and complexity of human breast tumors. A tumor model was\r\ndeveloped using primary breast tumor-initiating cells isolated from patient core biopsies that would more\r\naccurately reflect human breast cancer metastasis.\r\nMethods: Tumorspheres were isolated under serum-free culture conditions from core biopsies collected from five\r\npatients with clinical diagnosis of invasive ductal carcinoma (IDC). Isolated tumorspheres were transplanted into the\r\nmammary fat pad of NUDE mice to establish tumorigenicity in vivo. Tumors and metastatic lesions were analyzed\r\nby hematoxylin and eosin (H) staining and immunohistochemistry (IHC).\r\nResults: Tumorspheres were successfully isolated from all patient core biopsies, independent of the estrogen\r\nreceptor a (ERa)/progesterone receptor (PR)/Her2/neu status or tumor grade. Each tumorsphere was estimated to\r\ncontain 50-100 cells. Transplantation of 50 tumorspheres (1-5 Ã?â?? 103 cells) in combination with Matrigel into the\r\nmammary fat pad of NUDE mice resulted in small, palpable tumors that were sustained up to 12 months postinjection.\r\nTumors were serially transplanted three times by re-isolation of tumorspheres from the tumors and\r\ninjection into the mammary fat pad of NUDE mice. At 3 months post-injection, micrometastases to the lung, liver,\r\nkidneys, brain and femur were detected by measuring content of human chromosome 17. Visible macrometastases\r\nwere detected in the lung, liver and kidneys by 6 months post-injection. Primary tumors variably expressed\r\ncytokeratins, Her2/neu, cytoplasmic E-cadherin, nuclear b catenin and fibronectin but were negative for ERa and\r\nvimentin. In lung and liver metastases, variable redistribution of E-cadherin and b catenin to the membrane of\r\ntumor cells was observed. ERa was re-expressed in lung metastatic cells in two of five samples.\r\nConclusions: Tumorspheres isolated under defined culture conditions from patient core biopsies were tumorigenic\r\nwhen transplanted into the mammary fat pad of NUDE mice, and metastasized to multiple mouse organs.\r\nMicrometastases in mouse organs demonstrated a dormancy period prior to outgrowth of macrometastases. The\r\ndevelopment of macrometastases with organ-specific phenotypic distinctions provides a superior model for the\r\ninvestigation of organ-specific effects on metastatic cancer cell survival and growth....
Background: The frequency of E-cadherin germline mutations in countries with different incidence rates for gastric\r\ncarcinoma has not been well established. The goal of this study was to assess the worldwide frequency of CDH1\r\ngermline mutations in gastric cancers coming from low- and high-risk areas.\r\nMethods: English articles using MEDLINE access (from 1998 to 2011). Search terms included CDH1, E-cadherin,\r\ngermline mutation, gastric cancer, hereditary, familial and diffuse histotype.\r\nThe study included all E-cadherin germline mutations identified in gastric cancer patients; somatic mutations and\r\ngermline mutations reported in other tumors were excluded.\r\nThe method of this study was scheduled in accordance with the ââ?¬Å?PRISMA statement for reporting systematic\r\nreviews and meta-analysesââ?¬Â. Countries were classified as low- or middle/high risk-areas for gastric carcinoma\r\nincidence. Statistical analysis was performed to correlate the CDH1 mutation frequency with gastric cancer\r\nincidence areas.\r\nResults: A total of 122 E-cadherin germline mutations have been identified; the majority (87.5%) occurred in\r\ngastric cancers coming from low-risk areas. In high-risk areas, we identified 16 mutations in which missense\r\nmutations were predominant. (68.8%). We verified a significant association between the mutation frequency and\r\nthe gastric cancer risk area (p < 0.001: overall identified mutations in low- vs. middle/high-risk areas).\r\nConclusions: E-cadherin genetic screenings performed in low-risk areas for gastric cancer identified a higher\r\nfrequency of CDH1 germline mutations. This data could open new approaches in the gastric cancer prevention\r\ntest; before proposing a proband candidate for the CDH1 genetic screening, geographic variability, alongside the\r\nfamily history should be considered....
Background: Molecular alterations occur frequently in T-ALL and the potential impact of those abnormalities on\r\noutcome is still controversial. The current study aimed to test whether NOTCH1 mutations and additional molecular\r\nabnormalities would impact T-ALL outcome in a series of 138 T-ALL paediatric cases.\r\nMethods: T-ALL subtypes, status of SIL-TAL1 fusion, ectopic expression of TLX3, and mutations in FBXW7, KRAS,\r\nPTEN and NOTCH1 were assessed as overall survival (OS) and event-free survival (EFS) prognostic factors. OS and\r\nEFS were determined using the Kaplan-Meier method and compared using the log-rank test.\r\nResults: The frequencies of mutations were 43.5% for NOTCH1, while FBXW7, KRAS and PTEN exhibited frequencies\r\nof 19.1%, 9.5% and 9.4%, respectively. In 78.3% of cases, the coexistence of NOTCH1 mutations and other molecular\r\nalterations was observed. In multivariate analysis no statistical association was revealed between NOTCH1 mutations\r\nand any other variable analyzed. The mean length of the follow-up was 68.4 months and the OS was 50.7%. SILTAL1\r\nwas identified as an adverse prognostic factor. NOTCH1 mutation status was not associated with outcome,\r\nwhile the presence of NOTCH1 complex mutations (indels) were associated with a longer overall survival (p =\r\n0.031) than point mutations.\r\nConclusion: NOTCH1 mutations alone or in combination with FBXW7 did not impact T-ALL prognosis.\r\nNevertheless, complex NOTCH1 mutations appear to have a positive impact on OS and the SIL-TAL1 fusion was\r\nvalidated as a negative prognostic marker in our series of T-ALL....
Background: Major changes in the incidence of oesophageal and gastric cancers have been reported\r\ninternationally. This study describes recent trends in incidence and survival of subgroups of oesophageal and\r\ngastric cancer in England between 1998 and 2007 and considers the implications for cancer services and policy.\r\nMethods: Data on 133,804 English patients diagnosed with oesophageal and gastric cancer between 1998 and\r\n2007 were extracted from the National Cancer Data Repository. Using information on anatomical site and tumour\r\nmorphology, data were divided into six groups; upper and middle oesophagus, lower oesophagus, oesophagus\r\nwith an unspecified anatomical site, cardia, non-cardia stomach, and stomach with an unspecified anatomical site.\r\nAge-standardised incidence rates (per 100,000 European standard population) were calculated for each group by\r\nyear of diagnosis and by socioeconomic deprivation. Survival was estimated using the Kaplan-Meier method.\r\nResults: The majority of oesophageal cancers were in the lower third of the oesophagus (58%). Stomach with an\r\nunspecified anatomical site was the largest gastric cancer group (53%). The incidence of lower oesophageal cancer\r\nincreased between 1998 and 2002 and remained stable thereafter. The incidence of cancer of the cardia, noncardia\r\nstomach, and stomach with an unspecified anatomical site declined over the 10 year period. Both lower\r\noesophageal and cardia cancers had a much higher incidence in males compared with females (M:F 4:1). The\r\nincidence was also higher in the most deprived quintiles for all six cancer groups. Survival was poor in all subgroups\r\nwith 1 year survival ranging from 14.8-40.8% and 5 year survival ranging from 3.7-15.6%.\r\nConclusions: An increased focus on prevention and early diagnosis, especially in deprived areas and in males, is\r\nrequired to improve outcomes for these cancers. Improved recording of tumour site, stage and morphology and\r\nthe evaluation of focused early diagnosis programmes are also needed. The poor long-term survival reinforces the\r\nneed for early detection and multidisciplinary care....
Background: We specifically tested the aetiological hypothesis that a factor influencing geographical or temporal\r\nheterogeneity of childhood central nervous system (CNS) tumour incidence was related to exposure to a transient\r\nenvironmental agent.\r\nMethods: Information was extracted on individuals aged 0-14 years, diagnosed with a CNS tumour between the\r\n1st January 1974 and 31st December 2006 from the Yorkshire Specialist Register of Cancer in Children and Young\r\nPeople. Ordnance Survey eight-digit grid references were allocated to each case with respect to addresses at the\r\ntime of birth and the time of diagnosis, locating each address to within 0.1 km. The following diagnostic groups\r\nwere specified a priori for analysis: ependymoma; astrocytoma; primitive neuroectodermal tumours (PNETs); other\r\ngliomas; total CNS tumours. We applied the K-function method for testing global space-time clustering using fixed\r\ngeographical distance thresholds. Tests were repeated using variable nearest neighbour (NN) thresholds.\r\nResults: There was statistically significant global space-time clustering for PNETs only, based on time and place of\r\ndiagnosis (P = 0.03 and 0.01 using the fixed geographical distance and the variable NN threshold versions of the Kfunction\r\nmethod respectively).\r\nConclusions: There was some evidence for a transient environmental component to the aetiology of PNETs.\r\nHowever, a possible role for chance cannot be excluded....
Background: In colorectal carcinoma, extensive gene promoter hypermethylation is called the CpG island\r\nmethylator phenotype (CIMP). Explaining why studies on CIMP and survival yield conflicting results is essential.\r\nMost experiments to measure DNA methylation rely on the sodium bisulfite conversion of unmethylated cytosines\r\ninto uracils. No study has evaluated the performance of bisulfite conversion and methylation levels from matched\r\ncryo-preserved and Formalin-Fixed Paraffin Embedded (FFPE) samples using pyrosequencing.\r\nMethods: Couples of matched cryo-preserved and FFPE samples from 40 colon adenocarcinomas were analyzed.\r\nRates of bisulfite conversion and levels of methylation of LINE-1, MLH1 and MGMT markers were measured.\r\nResults: For the reproducibility of bisulfite conversion, the mean of bisulfite-to-bisulfite standard deviation (SD) was\r\n1.3%. The mean of run-to-run SD of PCR/pyrosequencing was 0.9%. Of the 40 DNA couples, only 67.5%, 55.0%, and\r\n57.5% of FFPE DNA were interpretable for LINE-1, MLH1, and MGMT markers, respectively, after the first analysis. On\r\nfrozen samples the proportion of well converted samples was 95.0%, 97.4% and 87.2% respectively. For DNA\r\nshowing a total bisulfite conversion, 8 couples (27.6%) for LINE-1, 4 couples (15.4%) for MLH1 and 8 couples (25.8%)\r\nfor MGMT displayed significant differences in methylation levels.\r\nConclusions: Frozen samples gave reproducible results for bisulfite conversion and reliable methylation levels. FFPE\r\nsamples gave unsatisfactory and non reproducible bisulfite conversions leading to random results for methylation\r\nlevels. The use of FFPE collections to assess DNA methylation by bisulfite methods must not be recommended.\r\nThis can partly explain the conflicting results on the prognosis of CIMP colon cancers....
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