Enhancer of zeste homologue 2 (EZH2) is a member of the Polycomb group of genes that is involved in epigenetic silencing and cell cycle regulation.
We studied EZH2 expression in 409 patients with ...colorectal cancer stages II and III. The patients were included in a randomised study, and treated with surgery alone or surgery followed by adjuvant chemotherapy.
EZH2 expression was significantly related to increased tumour cell proliferation, as assessed by Ki-67 expression. In colon cancer, strong EZH2 expression (P=0.041) and high proliferation (>or=40%; P=0.001) were both associated with better relapse-free survival (RFS). In contrast, no such associations were found among rectal cancers. High Ki-67 staining was associated with improved RFS in colon cancer patients who received adjuvant chemotherapy (P=0.001), but not among those who were treated by surgery alone (P=0.087). In colon cancers stage III, a significant association between RFS and randomisation group was found in patients with high proliferation (P=0.046), but not in patients with low proliferation (P=0.26). Multivariate analyses of colon cancers showed that stage III (hazard ratio (HR) 4.00) and high histological grade (HR 1.80) were independent predictors of reduced RFS, whereas high proliferation indicated improved RFS (HR 0.55).
Strong EZH2 expression and high proliferation are associated features and both indicate improved RFS in colon cancer, but not so in rectal cancer.
MicroRNAs (miRNAs) are important regulators of cellular processes and are found to be deregulated in many cancers. We here analysed the miRNA expression in anal carcinomas. In a previous study, we ...found that our anal carcinoma tumours were divided into two groups based on the expression of E2F-regulated genes. Therefore, we searched for miRNAs that could reproduce this grouping.
A global screen of the miRNA population was performed using real-time quantitative PCR (RT-qPCR) array methods and differentially expressed miRNAs were identified. Real-time-qPCR was used to verify the expression levels of selected miRNAs and genes in a larger collection of biopsies. A siRNA-mediated knockdown of human papilloma virus (HPV)16 E7 in a cervical cell line was performed to assess the effect of E7 on miR-15b.
The grouping of tumours into two groups based on the expression of E2F-controlled genes was confirmed in a larger collection of anal carcinoma tumours. The expression of miR-15b was shown to be highly correlated with that of five selected E2F-induced genes (CCNA2, CCNB1, CCNB2, MSH6 and MCM7). A knockdown of HPV16 E7 resulted in decreased levels of miR-15b in Ca Ski cells.
MiR-15b expression correlates with E2F-regulated genes in anal carcinoma and appears to be part of the E2F-regulatory network.
The aim of this study was to investigate the value of the cyclin D1 isoforms D1a and D1b as prognostic factors and their relevance as predictors of response to adjuvant chemotherapy with ...5-fluorouracil and levamisole (5-FU/LEV) in colorectal cancer (CRC).
Protein expression of nuclear cyclin D1a and D1b was assessed by immunohistochemistry in 335 CRC patients treated with surgery alone or with adjuvant therapy using 5-FU/LEV. The prognostic and predictive value of these two molecular markers and clinicopathological factors were evaluated statistically in univariate and multivariate survival analyses.
Neither cyclin D1a nor D1b showed any prognostic value in CRC or colon cancer patients. However, high cyclin D1a predicted benefit from adjuvant therapy measured in 5-year relapse-free survival (RFS) and CRC-specific survival (CSS) compared to surgery alone in colon cancer (P=0.012 and P=0.038, respectively) and especially in colon cancer stage III patients (P=0.005 and P=0.019, respectively) in univariate analyses. An interaction between treatment group and cyclin D1a could be shown for RFS (P=0.004) and CSS (P=0.025) in multivariate analysis.
Our study identifies high cyclin D1a protein expression as a positive predictive factor for the benefit of adjuvant 5-FU/LEV treatment in colon cancer, particularly in stage III colon cancer.
Inadequate molecular and clinical stratification of the patients with high-risk diffuse large B-cell lymphoma (DLBCL) is a clinical challenge hampering the establishment of personalized therapeutic ...options. We studied the translational significance of liquid biopsy in a uniformly treated trial cohort. Pretreatment circulating tumor DNA (ctDNA) revealed hidden clinical and biological heterogeneity, and high ctDNA burden determined increased risk of relapse and death independently of conventional risk factors. Genomic dissection of pretreatment ctDNA revealed translationally relevant phenotypic, molecular, and prognostic information that extended beyond diagnostic tissue biopsies. During therapy, chemorefractory lymphomas exhibited diverging ctDNA kinetics, whereas end-of-therapy negativity for minimal residual disease (MRD) characterized cured patients and resolved clinical enigmas, including false residual PET positivity. Furthermore, we discovered fragmentation disparities in the cell-free DNA that characterize lymphoma-derived ctDNA and, as a proof-of-concept for their clinical application, used machine learning to show that end-of-therapy fragmentation patterns predict outcome. Altogether, we have discovered novel molecular determinants in the liquid biopsy that can noninvasively guide treatment decisions.
•Quantitative, mutational, and fragmentation features in the ctDNA dynamically predict treatment responses and survival.•ctDNA captures the complete lymphoma ecosystem that extends beyond tumor biopsies, imaging, and clinical estimates.
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Many patients with aggressive B-cell lymphomas and high clinical risk score still die of lymphoma after conventional R-CHOP chemoimmunotherapy. We hypothesized that intensified chemoimmunotherapy ...including systemic central nervous system (CNS) prophylaxis improves outcome and reduces the incidence of CNS-related events.
Inclusion criteria were age 18–65 years, primary diffuse large B-cell lymphoma or grade III follicular lymphoma without clinical signs of CNS disease and negative cerebrospinal fluid cytology, age-adjusted International Prognostic Index 2–3 and WHO performance score 0–3. Treatment consisted of six courses of R-CHOEP-14 followed by a course of high-dose cytarabine and a course of high-dose methotrexate. Primary end point was failure-free survival (FFS) at 3 years.
A total of 156 eligible patients with a median age of 54 years (range 20–64) were included. Three toxic deaths were observed. Three-year overall survival (OS) and FFS rates (median observation time 52 months for survivors) were 81% and 65%, respectively. Seven patients experienced CNS relapse, all within 6 months.
The results are promising with favorable 3-year OS and FFS rates, a low toxic death rate and a lower than expected number of CNS events. CNS progression might be further reduced by earlier CNS prophylaxis.
NCT01502982.
Background This study examined employment patterns and associated factors in lymphoma survivors treated with high-dose chemotherapy with autologous stem cell transplantation (HDT-ASCT) from diagnosis ...to a follow-up survey at a mean of 10 years after HDT-ASCT. Patients and methods All lymphoma survivors aged ≥18 years at HDT-ASCT in Norway from 1987 to 2008, and alive at the end of 2011 were eligible for this cross-sectional study performed in 2012/2013. Participants completed a mailed questionnaire. Job status was dichotomized as either employed (paid work) or not-employed (disability and retirement pension, on economic support, home-makers, or students). Results The response rate was 78%, and the sample (N = 312) contained 60% men. Mean age at HDT-ASCT was 44.3 and at survey 54.0 years. At diagnosis 85% of survivors were employed, 77% before and 77% after HDT-ASCT, and 58% at follow-up. Forty seven percent of the survivors were employed at all time points. The not-employed group at survey was significantly older and included significantly more females than the employed group. No significant between-group differences were observed for lymphoma-related variables. Fatigue, mental distress and type D personality were significantly higher among those not-employed, while quality of life was significantly lower compared to the employed group. Older age at survey, being female, work ability and presence of type D personality remained significantly related to being not-employed at survey in the multivariable analysis. Conclusions Our findings show that not-employed long-term survivors after HDT-ASCT for lymphoma have more comorbidity, cognitive problems and higher levels of anxiety/depression than employed survivors. These factors should be checked and eventually treated in order to improve work ability.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Our purpose was to investigate if dysregulation of cell adhesion molecules could be linked to prognosis in squamous cell carcinomas (SCCs) of the anal region.
Protein expression of desmoglein-1 ...(DSG1), desmocollin-1 (DSC1) and E-cadherin was studied by immunohistochemistry in a cohort of 53 anal carcinoma patients treated by radiation alone or combined with 5-fluorouracil and mitomycin C.
Univariate analyses identified, among others, negative membranous DSG1 staining (P=0.009), negative cytoplasmic DSC1 staining (P=0.012) and negative DSG1 (membranous)+negative DSC1 (cytoplasmic) staining (P=0.004) to be associated with improved cancer-specific survival (CSS). On multivariate analyses positive DSG1 (membranous)+DSC1 (cytoplasmic) staining (HR 6.95, P=0.044), large tumour size and lymph node metastases (HR 6.44, P=0.004) and radiation without chemotherapy (HR 6.73 P=0.004) were associated with worse CSS. On univariate analysis, improved disease-free survival was associated with negative membranous staining of DSG1 (P=0.047), and negative DSG1 (membranous)+negative DSC1 (cytoplasmic) staining (P=0.025), among others.
Membrane negativity for DSG1 and cytoplasmic negativity for DSC1 are favourable markers for CSS in SCCs of the anal region.
Pseudoprogression in high-grade glioma Knudsen-Baas, K. M.; Moen, G.; Fluge, Ø. ...
Acta neurologica Scandinavica,
01/2013, Letnik:
127, Številka:
s196
Journal Article
Recenzirano
Pseudoprogression is a treatment‐related effect seen on imaging in high‐grade glioma. Enhancement of gadolinium contrast on control MRI can be misinterpreted as tumor recurrence and is also difficult ...to distinguish from radiation necrosis. Pseudoprogression is seen in up to 30% after standard treatment for glioblastoma multiforme (GBM), which is radiotherapy concurrent with chemotherapy with temozolomide (TMZ) and adjuvant cycles of TMZ. In this article, the current literature on pseudoprogression in high‐grade glioma is reviewed by searches in PubMed. We also present two clinical cases, one of which had medullary pseudoprogression. No articles on this subentity of pseudoprogression were found in PubMed. Standard MRI with gadolinium contrast cannot differentiate between pseudoprogression, tumor recurrence and radiation necrosis. More advanced imaging techniques are often not available. Pseudoprogression seems to be related to methylated promoter of the O6‐ methyl‐guanine methyl transferase (MGMT) gene, which is associated with improved treatment effect. Discontinuation or change of therapy on the basis of misinterpretation of MRI as disease progression is thus unfortunate. MRI should be interpreted with caution the first 6 months after standard treatment of high‐grade glioma. In a GBM patient with contrast enhancement on MRI but few or no new symptoms and/or stable steroid doses, treatment should be continued and control imaging performed after 2–3 months.
The Nordic Lymphoma Group has conducted a phase ll trial in newly diagnosed primary central nervous system lymphoma patients applying an age-adjusted multi-agent immunochemotherapy regimen, which in ...elderly patients included temozolomide maintenance treatment. Patients aged 18-75 years were eligible. Thirty-nine patients aged 18-65 years and 27 patients aged 66-75 years were enrolled. The median age of the two age groups was 55 and 70 years, respectively. The overall response rate was 73.8% for the entire cohort: 69.9% in the younger and 80.8% in the elderly subgroup. With a median follow up of 22 months, the 2-year overall survival probability was 60.7% in patients aged 65 years or under and 55.6% in patients aged over 65 years (P=0.40). The estimated progression-free survival at two years was 33.1% (95%CI: 19.1%-47.9%) in patients aged under 65 years and 44.4% (95%CI: 25.6%-61.8%) in the elderly subgroup (P=0.74). Median duration of response was ten months in the younger subgroup, and not reached in the elderly patient subgroup (P=0.33). Four patients aged 64-75 years (6%) died from treatment-related complications. Survival in the two age groups was similar despite a de-escalation of induction treatment in patients aged over 65 years. Duration of response in elderly patients receiving maintenance temozolomide was longer than in the younger age subgroup. While toxicity during induction is still of concern, especially in the elderly patients, we conclude from these data that de-escalation of induction therapy in elderly primary central nervous system lymphoma patients followed by maintenance treatment seems to be a promising treatment strategy. (clinicaltrials.gov identifier:01458730).
Human papillomavirus (HPV) is a major aetiological agent in anal carcinomas. We here present a study of global gene expression using microarray hybridisation in a collection of anal carcinoma ...biopsies. Quantitative PCR was used to verify expression of selected genes. All biopsies contained integrated DNA of human papillomavirus subtype 16 (HPV16) and expressed HPV16 E7 mRNA. No other subspecies of HPV were detected in these 13 biopsies as assessed by PCR amplification and DNA sequencing. Unsupervised cluster analysis, based on global mRNA expression, divided the tumour biopsies into two distinct groups. Cluster analysis based on a number of high-risk HPV and/or E2F-regulated genes reproduced this biopsy grouping, suggesting that integrated HPV16 substantially influenced global gene expression in approximately half the biopsies studied. The levels of HPV16 E7 mRNA were significantly different between the two groups, but with considerable overlap. Thus, influence on global gene expression could not be absolutely ascribed to the expression level of HPV16. To investigate whether this distinction in gene expression had prognostic impact, we studied protein expression in an independent cohort of 55 anal carcinomas not included in the microarray study of two differentially expressed candidate genes, minichromosome maintenance complex component 7 (MCM7) and cyclin-dependent kinase inhibitor 2A (CDKN2A or p16). HPV status was assessed by in situ hybridisation. There was a significant association between in situ staining for HPV E7 mRNA and immunostaining for CDKN2A (p16) and MCM7 protein. CDKN2A (p16) mRNA was found significantly differentially expressed between the two tumour groups. However, cluster analysis on genes directly regulated by CDKN2A (p16) could not reproduce this split of biopsies into two groups, suggesting that the transcriptional regulatory activity of CDKN2A in these biopsies is inhibited. Furthermore, protein expression of CDKN2A (p16) could not be associated with survival. MCM7 is directly regulated by E2F and induced by HPV, and its mRNA was found differentially expressed between the two tumour groups. High level of MCM7 protein was found to be associated with both improved relapse-free survival (RFS, P=0.02) and cancer-specific survival (CSS, P=0.03) in anal cancer patients treated with radiation with or without additional chemotherapy.
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