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Histone H2AX undergoes phosphorylation as an answer to DNA double-strand breaks, which in turn are part of the oncogenic procedure. The detection of gamma-H2AX can potentially serve as a biomarker for transformation of normal tissue to premalignant and consequently to malignant tissues. The aim of this study was to evaluate the clinical significance of gamma-H2AX expression in breast cancer. Gamma-H2AX expression in tissues from 110 breast cancer patients was analyzed by immunohistochemistry and correlated with clinicopathological variables. Greater tumor size, higher grade, and the number of affected lymph nodes are significantly associated with greater values of gamma-H2AX. In addition, gamma-H2AX differs significantly among patients’ International Federation of Gynecology and Obstetrics stage. Higher values of estrogen receptor and progesterone receptor are significantly associated with lower gamma-H2AX values. In conclusion, a positive association between gamma-H2AX expression and infaust histopathological parameters was observed. © The Author(s) 2019.

Pathogenesis and progression of lung cancer are governed by complex interactions between the environment and host genetic susceptibility, which is further modulated by genetic and epigenetic changes. Autotaxin (ATX, ENPP2) is a secreted glycoprotein that catalyzes the extracellular production of lysophosphatidic acid (LPA), a growth-factor-like phospholipid that is further regulated by phospholipid phosphatases (PLPP). LPA's pleiotropic effects in almost all cell types are mediated through at least six G-protein coupled LPA receptors (LPAR) that exhibit overlapping specificities, widespread distribution, and differential expression profiles. Here we use both preclinical models of lung cancer and clinical samples (from patients and healthy controls) to investigate the expression levels, activity, and biological role of the above components of the ATX/LPA axis in lung cancer. ENPP2 was genetically altered in8%of patients with lung cancer, whereas increased ATX staining and activity were detected in patient biopsies and sera, respectively. Moreover, PLPP3 expression was consistently downregulated in patients with lung cancer. Comparable observations were made in the two most widely used animal models of lung cancer, the carcinogen urethane-induced and the genetically engineered K-rasG12D-driven models, where genetic deletion of Enpp2 or Lpar1 resulted in disease attenuation, thus confirming a procarcinogenic role of LPA signaling in the lung. Expression profiling data analysis suggested that metabolic rewiring may be implicated in the procarcinogenic effects of the ATX/LPA axis in K-ras-G12D-driven lung cancer pathogenesis. Significance: These findings establish the role of ATX/LPA in lung carcinogenesis, thus expanding the mechanistic links between pulmonary fibrosis and cancer. © 2018 AACR.

Background-Aim: To evaluate the prognostic role of elaborate molecular clusters encompassing cyclin D1, cyclin E1, p21, p27 and p53 in the context of various breast cancer subtypes. Methods: Cyclin E1, cyclin D1, p53, p21 and p27 were evaluated with immunohistochemistry in 1077 formalin-fixed paraffin-embedded tissues from breast cancer patients who had been treated within clinical trials. Jaccard distances were computed for the markers and the resulted matrix was used for conducting unsupervised hierarchical clustering, in order to identify distinct groups correlating with prognosis. Results: Luminal B and triple-negative (TNBC) tumors presented with the highest and lowest levels of cyclin D1 expression, respectively. By contrast, TNBC frequently expressed Cyclin E1, whereas ER-positive tumors did not. Absence of Cyclin D1 predicted for worse OS, while absence of Cyclin E1 for poorer DFS. The expression patterns of all examined proteins yielded 3 distinct clusters; (1) Cyclin D1 and/or E1 positive with moderate p21 expression; (2) Cyclin D1 and/or E1, and p27 positive, p53 protein negative; and, (3) Cyclin D1 or E1 positive, p53 positive, p21 and p27 negative or moderately positive. The 5-year DFS rates for clusters 1, 2 and 3 were 70.0%, 79.1%, 67.4% and OS 88.4%, 90.4%, 78.9%, respectively. Conclusions: It seems that the expression of cell cycle regulators in the absence of p53 protein is associated with favorable prognosis in operable breast cancer. © 2017 Zagouri et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Purpose: It is well recognized that breast cancer is a heterogeneous disease. The purpose of the current study was to classify patients according to the immunohistochemical phenotype of their tumors in an effort to evaluate the outcome of the respective groups of patients and specifically of those with triple-negative breast cancer (TNBC) following dose-dense sequential adjuvant chemotherapy. Methods: A total of 595 patients with high-risk breast cancer were treated with adjuvant anthracycline-based dose-dense sequential chemotherapy with or without paclitaxel in the context of a randomized study. ER, PgR, HER2, Ki67, EGFR, and CK5 protein expression were evaluated in 298 formalin-fixed paraffin-embedded tumor samples by immunohistochemistry (IHC). HER2 was also evaluated by chromogen in situ hybridization (CISH). HER2 status and Ki67 protein expression differentiated luminal IHC subtypes (luminal B tumors being HER2 and/or Ki67-positive). Results: Among the 298 tumors, the immunohistochemical panel classified 37 (12%) as luminal A, 198 (66%) as luminal B, 27 (9%) as HER2 enriched, and 36 (12%) as TNBC. The median follow-up time was 97 months. Patients with luminal A tumors had the best prognosis, with improved disease-free survival (log-rank, P = 0.033) and overall survival (P = 0.006) compared with the other three tumor subtypes. The three subtypes had an increased risk for relapse and death compared with luminal A in multivariate analysis, as well. No benefit from paclitaxel treatment was detected in any of the four subtypes or the total cohort. Hierarchical clustering based on mRNA expression of ER, PgR, and HER2 by quantitative RT-PCR identified patient groups that were comparable to the subtypes identified by IHC. Conclusions: The results of this study confirm that triple negative, luminal B and HER2-enriched phenotypes identified by IHC are of adverse prognostic value in high-risk breast cancer patients treated with dose-dense sequential adjuvant chemotherapy. © 2011 Springer-Verlag.

Journal URL: http://www.iiar-anticancer.org/main.php?id=2

Journal URL: http://carcin.oxfordjournals.org/

Journal URL: http://carcin.oxfordjournals.org/

Journal URL: http://carcin.oxfordjournals.org/

Objectives: To compare the detection of HER-2 status by real-time PCR, on paraffin-embedded breast carcinomas, in respect to immunohistochemistry (IHC) and chromogenic in situ hybridization (CISH). Design and methods: Paraffin-embedded breast carcinomas collected from 85 patients diagnosed with early stage breast cancer were analyzed for HER-2 gene amplification by real-time PCR and CISH, as well as for HER-2 protein expression by IHC. Results: HER-2 gene amplification was observed in 19 (22.4%) of 85 breast cancer patients by real-time PCR and in 19 (22.4%) of 85 patients by CISH. Strong (3+) HER-2 protein over-expression was observed in 13 (15.3%) out of 85 patients. Moreover, there were 4 out of 85 (4.7%) patients that had moderate (2+) HER-2 protein over-expression, while 68 out of 85 (80%) patients had no HER-2 protein over-expression by IHC. There were strong concordance rates between real-time PCR and IHC (79/85, 92.9%, p < 0.0001) and real-time PCR and CISH (77/85, 90.6%, p < 0.0001). The concordance rate between the three methods was 90.6% (p < 0.0001). Conclusions: Our data show that the results obtained for amplification of HER-2 by real-time PCR on the LightCycler are comparable to those obtained by IHC and CISH. © 2006 The Canadian Society of Clinical Chemists.

Background. Fibrosis, the replacement of functional tissue with excessive fibrous tissue, can occur in all the main tissues and organ systems, resulting in various pathological disorders. Idiopathic Pulmonary Fibrosis is a prototype fibrotic disease involving abnormal wound healing in response to multiple sites of ongoing alveolar epithelial injury. Methodology/Principal Findings. To decipher the role of TNF and TNF-mediated inflammation in the development of fibrosis, we have utilized the bleomycin-induced animal model of Pulmonary Fibrosis and a series of genetically modified mice lacking components of TNF signaling. Transmembrane TNF expression is shown to be sufficient to elicit an inflammatory response, but inadequate for the transition to the fibrotic phase of the disease. Soluble TNF expression is shown to be crucial for lymphocyte recruitment, a prerequisite for TGF-b1 expression and the development of fibrotic lesions. Moreover, through a series of bone marrow transfers, the necessary TNF expression is shown to originate from the non-hematopoietic compartment further localized in apoptosing epithelial cells. Conclusions. These results suggest a primary detrimental role of soluble TNF in the pathologic cascade, separating it from the beneficial role of transmembrane TNF, and indicate the importance of assessing the efficacy of soluble TNF antagonists in the treatment of Idiopathic Pulmonary Fibrosis. © 2006 Oikonomou et al.

Researchers worldwide with information about the Kirsten ras (Ki-ras) tumour genotype and outcome of patients with colorectal cancer were invited to provide that data in a schematized format for inclusion in a collaborative database called RASCAL (The Kirsten ras in-colorectal-cancer collaborative group). Our results from 2721 such patients have been presented previously and for the first time in any common cancer, showed conclusively that different gene mutations have different impacts on outcome, even when the mutations occur at the same site on the genome. To explore the effect of Ki-ras mutations at different stages of colorectal cancer, more patients were recruited to the database, which was reanalysed when information on 4268 patients from 42 centres in 21 countries had been entered. After predetermined exclusion criteria were applied, data on 3439 patients were entered into a multivariate analysis. This found that of the 12 possible mutations on codons 12 and 13 of Kirsten ras, only one mutation on codon 12, glycine to valine, found in 8.6% of all patients, had a statistically significant impact on failure-free survival (P = 0.004, HR 1.3) and overall survival (P = 0.008, HR 1.29). This mutation appeared to have a greater impact on outcome in Dukes’ C cancers (failure-free survival. P = 0.008, HR 1.5; overall survival P = 0.02, HR 1.45) than in Dukes’ B tumours (failure-free survival, P = 0.46, HR 1.12; overall survival P = 0.36, HR 1.15). Ki-ras mutations may occur early in the development of pre-cancerous adenomas in the colon and rectum. However, this collaborative study suggests that not only is the presence of a codon 12 glycine to valine mutation important for cancer progression but also that it may predispose to more aggressive biological behaviour in patients with advanced colorectal cancer. (C) 2001 Cancer Research Campaign.

The mutagenic, carcinogenic and cytotoxic activity of dacarbazine, a drug employed in cancer chemotherapy, may be related to the induction in DNA of O-6-methylguanine (O-6-meG), a quantitatively minor but biologically important lesion, In the present study the kinetics of O-6-meG formation and repair in blood leukocyte DNA were examined in 20 Hodgkin’s lymphoma patients treated i.v. with 180 +/- 13 (mean +/- SD) mg/m(2) dacarbazine and compared with those observed in various tissues of rodents treated with different doses of the drug, In Hodgkin’s lymphoma patients adduct levels reached a value of 0.27 +/- 0.14 fmol/mu g DNA 2 h after dacarbazine administration, while the rate of subsequent loss suggested an adduct half-life of less than or equal to 30 h, Measurement of adduct levels in the same individuals after successive courses of treatment spaced 3 weeks apart (up to 10 treatment courses) demonstrated a consistent individual response and statistical analysis of variance confirmed that intra-individual variation in adduct accumulation after a given dose of dacarbazine accounted for only 5% of the total variance observed, In contrast, inter-individual variation accounted for 70% of the observed variance, with adduct levels 2 h after drug treatment varying similar to 7.5-fold among adduct-positive individuals. No significant depletion of lymphocyte O-6-alkylguanine-DNA alkyltransferase (AGT) occurred after patient treatment with dacarbazine. No significant relationship between adduct levels and clinical response to treatment was observed, In rats treated with single or multiple doses of dacarbazine causing varying degrees of AGT depletion the highest levels of O-6-meG were seen in the liver followed by the lymph nodes, bone marrow and blood leukocytes, which showed up to similar to 2-fold lower levels, A similar tissue distribution was also observed in mice and in a single rabbit, These observations suggest that O-6-meG levels assayed in blood leukocytes of therapeutically treated humans reflect those present in the lymph nodes (target tissue for chemotherapy) and the bone marrow (target tissue for leukaemogenesis) and may be utilized as a measure of the drug dose reaching these tissues, The quantitative data reported in this study show that under conditions of no depletion of;AGT O-6-meG accumulates in blood leukocyte DNA of humans at a rate similar to that observed in rats, suggesting that human susceptibility to any O-6-meG-mediated genotoxic effects of dacarbazine may be comparable with that of the rat.

The accumulation of O-6-methylguanine (O-6-meG) in the DNA of blood leukocytes of 21 Hodgkin’s lymphoma patients (followed for up to 12 cycles of treatment) treated in the context of MOPP combination chemotherapy with 150 mg procarbazine daily for 10 days was examined and compared to that observed in rats treated with different doses of procarbazine as a single agent once per day for 10 days. In humans, the adduct accumulated in a dose-related fashion and appeared to approach a steady-state after 7-8 days of treatment. Adduct levels on day 10 of the treatment cycle averaged 0.25 +/- 0.09 (mean +/- SD) mu mol/ molG and, for different individuals, covered a 3-fold range. Intra-individual variability between different treatment cycles was much more limited than inter-individual variability, the two parameters accounting for 8.9% and 84.5% respectively of adduct variance at a constant cumulative dose. Comparison of the dose-response relationships for humans and rats indicates that, under conditions of no depletion of O-6-alkylguanine-DNA alkyltransferase (AGT), O-6-meG accumulates in blood leukocyte DNA of humans at a rate which is only approximately 2-fold lower than in rats, implying that, to the extent to which O-6-meG contributes to the genotoxic activity of procarbazine, human susceptibility to it is likely to be comparable to that of the rat. This is likely to be true also of the bone marrow (the tissue of interest as a target tissue for leukaemogenesis), since the tissue distribution of O-6-meG induced by low doses of procarbazine in rats, mice and rabbits indicated that blood leukocyte levels of this adduct closely reflect those in the bone marrow. Based on these results, it is estimated that by the end of a MOPP chemotherapy cycle O-6-meG reaches levels of the order of 0.2-0.3 fmol/mu g DNA (0.3-0.5 mu mol/molG) in human bone marrow (the target tissue of leukaemogenesis observed after such treatment).

O6-Methylguanine has been measured in peripheral blood leukocytes of 14 patients during one or more cycles of treatment with procarbazine (daily treatment for 10 days) and in 12 patients during one or more cycles of treatment with dacarbazine (single dose per cycle). Adduct formation at levels up to about 0.4 fmole/mug DNA was detected in all procarbazine- and all but one dacarbazine-treated patients at some point after treatment. O6-Methylguanine accumulated during procarbazine treatment in a dose-related manner (mean rate of accumulation 2.8 x 10(-4) fmole/mug DNA per mg/m2 dose) and appeared to approach a plateau by the end of the cycle (above 600 mg/m2 cumulative dose). The average rate of O6-methylguanine formation 2 hr after dacarbazine treatment was 11 +/- 8 X 10(-4) fmole/mug DNA per mg/m2 dose. Individuals examined on more than one treatment cycle with either drug showed broadly similar methylation responses. The rate of adduct accumulation showed a nonsignificant, negative correlation with the pretreatment lymphocyte levels of the repair enzyme O6-alkylguanine-DNA alkyltransferase (AGT) in the case of procarbazine and no correlation in the case of dacarbazine. No consistent lymphocyte AGT depletion was noted as a result of treatment with either drug. No correlation between O6-methylguanine formation and hematological toxicity was observed. In eight patients showing full remission after treatment with dacarbazine, the value of O6-methylguanine (averaged over all the cycles) was 0.252 +/- 0.120 fmole/mug DNA while in four patients showing partial or no response it was 0.087 +/- 0.110 fmole/mug DNA (p < 0.05). One of the two nonresponding procarbazine-treated patients showed very low levels of O6-methylguanine during a cycle of observation of DNA adduct formation. Human blood leukocytes are about 5-fold less susceptible than those of the rat to accumulation of O6-methylguanine during exposure to procarbazine. Furthermore, similar adduct levels were found in rat peripheral blood leukocytes and lymphocytes, bone marrow, and lymph nodes, suggesting that levels observed in human blood leukocytes may reflect those in the presumed target tissues for the leukemogenic (bone marrow) and the therapeutic (lymph nodes) effects of procarbazine. The possible use of these observations in the assessment orcarcinogenic risks to humans exposed to procarbazine or environmental methylating agents such as dimethylnitrosamine is discussed.

The case of a young man with stage IV chemoresistant pure seminoma overexpressing KIT, who achieved complete remission (CR) after the administration of imatinib mesylate (400 mg once daily), along with a third-line chemotherapy regimen, consisting of paclitaxel (150 mg/m2), oxaliplatin (100 mg/m2) and gemcitabine (800 mg/m2) every 2 weeks with granulocyte colony-stimulating factor (G-CSF) support is reported. The patient had received first- and second-line regimens consisting of ifosfamide, bleomycin, etoposide cisplatin (5 cycles, every 3 weeks) and methotrexate, vinblastine, actinomycin D, cyclophosphamide, cisplatin (3 cycles, every 3 weeks) respectively, without having normalized beta-human chorionic gonadotrophin (beta-HCG) levels. Following treatment with imatinib plus third-line chemotherapy (paclitaxel, oxaliplatin, gemcitabine), the levels of beta-HCG were reduced to within the normal limits during the first month of treatment. Therefore, the patient underwent surgical resection of the residual disease from the retroperitoneum and liver, which proved to be only necrotic tissue. The patient is under close follow-up, with no evidence of disease, 36 months after the completion of chemotherapy and 32 months post surgery.

Journal URL: http://www.sciencedirect.com/science/journal/0361090X

Researchers worldwide with information about the Kirsten ras (Ki-ras) tumour genotype and outcome of patients with colorectal cancer were invited to provide that data in a schematized format for inclusion in a collaborative database called RASCAL (The Kirsten ras in-colorectal-cancer collaborative group). Our results from 2721 such patients have been presented previously and for the first time in any common cancer, showed conclusively that different gene mutations have different impacts on outcome, even when the mutations occur at the same site on the genome. To explore the effect of Ki-ras mutations at different stages of colorectal cancer, more patients were recruited to the database, which was reanalysed when information on 4268 patients from 42 centres in 21 countries had been entered. After predetermined exclusion criteria were applied, data on 3439 patients were entered into a multivariate analysis. This found that of the 12 possible mutations on codons 12 and 13 of Kirsten ras, only one mutation on codon 12, glycine to valine, found in 8.6% of all patients, had a statistically significant impact on failure-free survival (P = 0.004, HR 1.3) and overall survival (P = 0.008, HR 1.29). This mutation appeared to have a greater impact on outcome in Dukes’ C cancers (failure-free survival, P = 0.008, HR 1.5; overall survival P = 0.02, HR 1.45) than in Dukes’ B tumours (failure-free survival, P = 0.46, HR 1.12; overall survival P = 0.36, HR 1.15). Ki-ras mutations may occur early in the development of pre-cancerous adenomas in the colon and rectum. However, this collaborative study suggests that not only is the presence of a codon 12 glycine to valine mutation important for cancer progression but also that it may predispose to more aggressive biological behaviour in patients with advanced colorectal cancer. © 2001 Cancer Research Campaign http://www.bjcancer.com