The granulocyte-associated transcription factor Krüppel-like factor 5 is silenced by hypermethylation in acute myeloid leukemia

Krüppel-like factor 5 (KLF5) has been implicated as a tumor suppressor in various solid tumors such as breast and prostate, and recent studies have demonstrated a role for this protein in neutrophil differentiation of acute promyelocytic leukemia cells in response to ATRA. Here, we show that KLF5 expression increases during primary granulocyte differentiation and that expression of KLF5 is a requirement for granulocyte differentiation of 32D cells. In AML, we show that KLF5 mRNA expression levels are reduced in multiple French-American-British subtypes compared to normal controls, and also in leukemic stem cells relative to normal hematopoietic stem cells. We demonstrate that in selected AML cases, reduced expression is associated with hypermethylation of the KLF5 locus in the proximal promoter and/or intron 1, suggesting that this may represent a Class II genetic lesion in the development of AML.     

Hypoxia-inducible factor-1α protein expression is associated with poor survival in normal karyotype adult acute myeloid leukemia

We examined the predictive impact of HIF-1α protein expression on clinical outcome of 84 normal karyotype acute myeloid leukemia (NK-AML) patients (median age 66.5 years) at our institute. Thirty percent of NK-AML cells expressed cytoplasmic HIF-1α. In univariate analysis, low HIF-1α (≤5%, n = 66) was associated with improved event-free survival (p = 0.0453, HR = 0.22). Multivariate analysis incorporating age, complete remission, FLT3-ITD mutation, and marrow blast percentage demonstrated that HIF-1α was independently associated with poorer overall and event-free survival. HIF-1α expression correlated with VEGF-C but not VEGF-A, marrow angiogenesis, FLT3 ITD or NPM1 mutations. These results support HIF-1α as an outcome marker for NK-AML.     

The relevance of cell kinetics for optimal scheduling of 1-β-d-Arabinofuranosyl cytosine and methotrexate in a slow growing acute myeloid leukemia (BNML)

Summary 1--d-Arabinosyl cytosine and methotrexate were studied for their antitumor activity in acute myeloid leukemia of the BN rat (BNML), which is characterized by a slow growth rate due to the presence of a high proportion of nonproliferating cells.It was found that the two drugs showed the maximal cytotoxic action when given separately. The effect was highly dependent on the interval between the administration of each drug.The variation of the cell kinetic parameters produced by the recruitment into cycle of the resting population, as determined by labeling indices, correlates well with the antileukemic action of the drug combination.Abbreviations used Ara-C 1--d-arabinosyl cytosine - MTX methotrexate - ³H-TDR tritiated thymidine - LI labeling index     

Hypoxia-inducible factor 1α expression is a prognostic biomarker in patients with astrocytic tumors associated with necrosis on MR image

Hypoxia-inducible factor (HIF)-1α and HIF-2α expression were investigated immunohistochemically as determinants of prognosis in 42 cases of astrocytic tumors associated with necrosis grade on magnetic resonance (MR) imaging. Expression of HIF-1α was determined immunohistologically. The degree of necrosis on MR images was divided into four grades. Kaplan–Meier analysis revealed a significant effect of necrosis grade on MR images on cumulative overall survival. Median survival times were 26, 14, and 13 months for patients with necrosis grades 1, 2, and 3, respectively (not defined for grade 0). Kaplan–Meier analysis revealed a significant effect of HIF-1α expression on cumulative overall survival. Median survival time of patients with HIF-1α expression was 17 months, whereas it was 80 months for patients without HIF-1α expression. However, overexpression of HIF-2α did not correlate with malignant features, for example angiogenesis or necrosis, and had no impact on overall survival of patients with glial tumors. In conclusion, HIF-1α, but not HIF-2α, is a useful prognostic factor in astrocytic tumor associated with necrosis on MR images.     

Overall survival of Brazilian acute myeloid leukemia patients according to the European LeukemiaNet prognostic scoring system: a cross-sectional study

Prognostic stratification in acute myeloid leukemia (AML) relies, mostly, on cytogenetics and molecular features of leukemic blasts. The LeukemiaNet prognostic scoring system has been proposed as a standardized way of evaluating prognosis in AML. We have analysed outcomes in 65 AML cases (median age of 54 years, range 18–82) treated at five hematology centers in Brazil stritified according to the European Leukemia Net (ELN) recommendations for cytogenetic and molecular analysis. We classified patients as favorable (N?=?13), intermediate-1 (N?=?25), intermediate-2 (N?=?15), or adverse risk (N?=?9). Bone marrow transplantation (BMT) was performed in 13 patients (21%). Median follow-up was 12 months. The median overall survival (OS) for all patients was 12.4 months. Median OS was 19.8, 12.4, 10.1, and 10.4 months (p?=?0.24) for patients in the favorable, intermediate-1, intermediate-2, and adverse groups, respectively. Among patients receiving BMT, median OS was 26.8 months. The ELN is a valuable tool for prognostic stratification of AML patients treated in Brazil. Nevertheless, its usefulness is limited when compared to data from developed countries.     

Recurrent isochromosome 21 and multiple abnormalities in a patient suspected of having acute myeloid leukemia with eosinophilic differentiation—a rare case from South India

Acute myeloid leukemia (AML) is a phenotypically heterogeneous disorder. The M4 subtype of AML is frequently associated with the cytogenetic marker inversion 16 and/or the presence of eosinophilia. Blast crisis is the aggressive phase of the triphasic chronic myeloid leukemia (CML), which is a disease with Philadelphia (Ph) chromosome as the major abnormality. In the present study, we report a 76-year-old patient suspected of having AML with eosinophilic differentiation (AML-M4), which in clinical tests resembles CML blast crisis with multiple chromosomal abnormalities. Isochromosome 21 [i(21)(q10)] was the most recurrent feature noted in metaphases with 46 chromosomes. Ring chromosome, tetraploid endoreduplication, recurrent aneuploid clones with loss of X chromosome, monosomy 17, monosomy 7, and structural variation translocation (9;14) were also observed in this patient. Fluorescent in situ hybridization (FISH) confirmed the absence of Ph chromosome. This report shows how cytogenetic analyses revealed atypical structural aberrations in the M4 subtype of AML.     

Is extracapsular tumour spread a prognostic factor in patients with early breast cancer?

Background

This study searched for extra capsular tumour spread (ECS) as a prognostic factor for recurrence in terms of Disease Free Survival (DFS) and Overall Survival (OS).

Patients and methods

For this study, from a retrospective database of the Doubs cancer registry, 823 eligible women with node positive breast cancer treated from February 1984 to November 2000 were identified. The following factors were evaluated: ECS, numbers of involved nodes, histological tumour grade, tumour size, status of estrogen and progesterone receptors, and age of patient. A Cox proportional hazards method was used to search for significant factors related to OS and DFS length.

Results

In the multivariate analysis, factors related to DFS length were found to be: tumour grade (aHR 0.76, 95 % CI 0.61–0.96, p = 0.02), ECS status (aHR 0.7, 95 % CI 0.49–0.96, p = 0.03), progesterone (PgR) status (aHR 0.63, 95 % CI 0.44–0.85 p = 0.008), number of nodes involved (aHR 0.75, 95 % CI 0.56–1, p = 0.05). The multivariate analysis for OS found as significant factors: tumour grade (aHR 0.76, 95 % CI 0.61–0.95; p = 0.02) and PgR status (aHR 0.8, 95 % CI 0.56–0.99, p = 0.02).

Conclusions

This study might suggest taking into account ECS status in the adjuvant decision-making process.     

The expression of the novel CYP2W1 enzyme is an independent prognostic factor in colorectal cancer – A pilot study

AimCytochrome P450 (CYP) enzymes are important for drug metabolism. A novel cytochrome P450 enzyme, CYP2W1, has recently been identified. This enzyme is mainly found in foetal colon tissue and in tumour tissue. In this pilot study, we have investigated the expression of CYP2W1 in 162 tumours from patients with stages II and III colorectal cancer.MethodsThe expression of CYP2W1 enzyme was immunohistochemically detected using a polyclonal antibody. Staining intensity was defined using a visual grading scale from 0 to 3. Grades 0–2 were classified as low, and grade 3 was classified as high expression of CYP2W1.ResultsAbout 64% of the tumours expressed a low level of CYP2W1-expression, and 36% expressed a high level. CYP2W1-expression was an independent prognostic factor for overall survival (p = 0.007), where a high expression was associated with a worse clinical outcome.ConclusionsImmunohistochemically assessed expression of CYP2W1 is an independent prognostic factor in patients with stages II and III colorectal cancer.     

What is the value of hemoglobin as a prognostic and predictive factor in cancer?

Anemia is a frequently encountered complication in cancer, and is associated with fatigue and reduced quality of life. Retrospective analyses of data from patients with hematological malignancies and solid tumors provide evidence that a low baseline hemoglobin (Hb) level is a prognostic factor for poor outcome. Moreover, in some situations, low Hb is a negative predictive parameter in chemotherapy. The adverse impact of anemia has been documented in patients with lymphomas and leukemias, as well as in those with non–small-cell lung cancer, ovarian cancer, cervical cancer, renal cell carcinoma, head and neck cancer and other solid tumors. Studies in animal models support the role of low Hb levels as a negative prognostic and predictive factor. Although prospective clinical trials are still needed to confirm that Hb levels affect outcome, the available evidence suggests that there is more than one reason to pay attention to Hb levels in cancer patients: increasing Hb not only corrects anemia and thereby improves physical functioning and quality of life, but also may improve clinical outcomes.     

The negative impact of antibiotics on outcomes in cancer patients treated with immunotherapy: a new independent prognostic factor?

Immune-checkpoint inhibitors (ICI) now represent the standard of care for several cancer types. In pre-clinical models, absence of an intact gut microbiome negatively impacted ICI efficacy and these findings permitted to unravel the importance of the commensal microbiota in immuno-oncology. Recently, multiple clinical studies including more than 1800 patients in aggregate demonstrated the negative predictive impact of treatments with broad-spectrum antibiotics (ATB) on cancer patients receiving ICI. Altogether, these results have led to the hypothesis that ATB-induced dysbiosis might influence the clinical response through the modulation of the gut microbiome. Controversy still remains, as ATB treatment might simply constitute a surrogate marker of unfit or immunodeficient patients. In this review, we summarize recent publications addressing the impact of the gut microbiome on ICI efficacy, discuss currently available data on the effect of ATB administered in different time-frames respect to ICI initiation, and finally, evoke the therapeutic implications of these findings.     

TBLR1 is a novel prognostic marker and promotes epithelial–mesenchymal transition in cervical cancer

Background:

Invasion and metastasis remain a critical issue in cervical cancer. However, the underlying mechanism of it in cervical cancer remains unclear. The newly discovered protein, TBLR1, plays a crucial role in regulating various key cellular functions.

Methods:

In this study, western blot, real-time RT–PCR, immunohistochemical staining, 3D morphogenesis Matrigel culture, wound healing and Boyden chamber invasion assays, xenografted tumour model, luciferase assays, and chromatin immunoprecipitation assays were used.

Results:

The expression of TBLR1 in cervical cancer cell lines and tissues was significantly upregulated at both the RNA and protein levels compared with that in normal cervical cells. Statistical analysis suggested that TBLR1 as an independent prognostic factor was significantly correlated with the clinical stage, survival time and recurrence. Moreover, overexpression of TBLR1 in Hela and Siha cell lines promoted invasion in vitro and in vivo with the increases of the mesenchymal factors vimentin and fibronectin and decreases of the epithelial marker α-catenin. In contrast, RNAi-mediated knockdown of TBLR1 inhibited epithelial–mesenchymal transition in vitro and in vivo. Further study indicated that this might be mediated via the NF-κB and Wnt/β-Catenin signalling pathway, and involve regulation of Snail and Twist.

Conclusions:

The TBLR1 protein may be a prognostic marker in cervical cancer and play an important role in the invasion and metastasis of human cervical cancer.     

Is there a plateau in the survival curve after autologous transplantation in patients with intermediate and high-risk acute myeloid leukemia? A 20-year single institution experience

In an attempt to examine whether autologous SCT provides long-term disease control in patients with intermediate and high-risk AML where a suitable donor is not available, we analyzed the outcomes of autologous SCT in patients with intermediate and high-risk AML from 1986 to 2005. No relapses occurred after 2.2 years. The overall survival curve appears to have developed a plateau after 2.2 years. In conclusion, autologous SCT in patients with AML in whom an allogeneic transplantation is not feasible appears to be a safe alternative and a plateau in the survival curve indicates cure in a small proportion of patients.     

Elevated frequencies of CD4⁺ CD25⁺ CD127lo regulatory T cells is associated to poor prognosis in patients with acute myeloid leukemia

Regulatory T cells (Treg) mediate amelioration of disease and immune homeostasis by inhibiting immune activation and maintaining peripheral immune tolerance. The suppressive mechanisms and clinical significance of Treg have not been completely elucidated in patients with acute myeloid leukemia (AML). Here, we demonstrated that CD127 in combination with CD4 and CD25 can identify FoxP3(+) Treg in peripheral blood (PB) and bone marrow (BM) using multicolor flow cytometry. We showed that the CD4(+) CD25(+) CD127(lo) Treg frequencies were significantly increased and their phenotypes were different in PB from newly diagnosed AML patients compared to those from healthy volunteers (HVs). Moreover, the Treg frequencies were significantly higher in BM than those from PB in the same patients. The Treg frequencies were reduced when patients achieved complete remission (CR) and were increased when patients relapsed. The Treg frequencies at diagnosis in PB and BM of patients who had achieved CR were lower than those of patients who had persistent leukemia or died, respectively. CD4(+) CD25(+) Treg were isolated by magnetic-activated cell sorting and tested for suppressive functions in coculture with allogeneic carboxyfluorescein diacetate succinimidylester-labeled CD4(+) CD25(-) responder cells. Suppression mediated by Treg was higher in AML patients compared to HVs. No significant differences were observed in the cytokines production of Treg, including interferon-gamma (IFN-γ), interleukin (IL)-4,IL-2 and IL-10, between patients with AML and HVs. Our study suggests that Treg may play a role in the pathogenesis of AML, and sequential measurements of Treg frequency may have clinical value in the evaluation of therapeutic effects and clinical outcome.     

Granulocyte colony-stimulating factor after intensive consolidation chemotherapy in acute myeloid leukemia: results of a randomized trial of the Groupe Ouest-Est Leucémies Aigues Myeloblastiques.

PURPOSE: Ten years after the first clinical studies, the clinical impact of myeloid growth factors in acute myeloid leukemia is still unclear. One of the objectives of the Groupe Ouest-Est Leucémies Aigues Myeloblastiques (GOELAM) 2 trial was to evaluate the benefit of granulocyte colony-stimulating factor (GCSF) given only after the two courses of intensive consolidation chemotherapy (ICC) used to maintain complete remission (CR). PATIENTS AND METHODS: One hundred ninety-four patients who were in CR after induction treatment were randomly assigned to receive G-CSF (100 patients) or no G-CSF (94 patients) after two courses of ICC (ICC 1, high-dose cytarabine plus mitoxantrone; ICC 2, amsacrine plus etoposide). G-CSF (filgrastim) was administered from the day after chemotherapy until granulocyte recovery at a daily dose of 5 microg/kg. RESULTS: In the G-CSF group, the median duration of neutropenia (< 0.5 x 10(9)/L) was dramatically reduced, both after ICC 1 (12 v 19 days, P <.001) and after ICC 2 (20 v 28 days, P <.001). The median duration of hospitalization was also significantly shorter in the G-CSF group (24 v 27 days after ICC 1, P <.001; 29 v 34 days after ICC 2, P <. 001). The median duration of intravenous antibiotics was significantly reduced after ICC 1 and ICC 2, and the median duration of antifungal therapy was significantly reduced after ICC 1. However, the incidence of microbiologically documented infections, the toxic death rate, the 2-year disease-free survival, and the 2-year overall survival were not affected by G-CSF administration. Moreover, the median interval between ICC1 and ICC2 was reduced by only 2 days, and the number of patients undergoing ICC2 was not increased in the G-CSF arm. CONCLUSION: G-CSF should be administered routinely after ICC to reduce the duration of neutropenia and hospitalization. However, G-CSF did not seem to significantly increase the feasibility of this two-course program or modify overall outcome.