International Scoring System for Evaluating Prognosis in Myelodysplastic Syndromes

The World Health Organization (WHO) classification of the myeloid neoplasms.

Motivation: Predicting the metastatic potential of primary malignant tissues has direct bearing on the choice of therapy. Several microarray studies yielded gene sets whose expression profiles successfully predicted survival. Nevertheless, the overlap between these gene sets is almost zero. Such small overlaps were observed also in other complex diseases, and the variables that could account for the differences had evoked a wide interest. One of the main open questions in this context is whether the disparity can be attributed only to trivial reasons such as different technologies, different patients and different types of analyses.

Results: To answer this question, we concentrated on a single breast cancer dataset, and analyzed it by a single method, the one which was used by van't Veer et al. to produce a set of outcome-predictive genes. We showed that, in fact, the resulting set of genes is not unique; it is strongly influenced by the subset of patients used for gene selection. Many equally predictive lists could have been produced from the same analysis. Three main properties of the data explain this sensitivity: (1) many genes are correlated with survival; (2) the differences between these correlations are small; (3) the correlations fluctuate strongly when measured over different subsets of patients. A possible biological explanation for these properties is discussed.

Contact: eytan.domany@weizmann.ac.il

Supplementary information: http://www.weizmann.ac.il/physics/complex/compphys/downloads/liate/

/pdf/outcome-signature-genes-in-breast-cancer-is-there-a-unique-43j2y3gyl6.pdf

Outcome signature genes in breast cancer: is there a unique set?

Mantle cell lymphoma (MCL) is a B-cell neoplasm thought to derive from mantle zone B-cells and characterized by translocations involving the CCND1 gene, most commonly t(11;14)(q13;q23). The classical variant of MCL is comprised of small- to medium-sized cells with irregular nuclear contours. Aggressive variants of MCL include tumors composed of lymphoblast-like (blastoid) or pleomorphic cells.

Mantle Cell Lymphoma

Monoclonal antibody Ki-67 is a reliable and easy means of accurately assessing the growth fraction of human neoplasms. Although the number of long-term follow-up studies is limited, it does appear to provide valuable prognostic information particularly in lymphoproliferative disease. Since the estimation of growth fraction is only one factor influencing tumour behaviour it would be naive to believe that measurement of this parameter alone, no matter how accurately, would provide the clinician with definitive prognostic information for all tumours. The antibody is also of use in research, providing a means of measuring proliferative activity in a variety of conditions besides malignancy, and may prove of value in monitoring tumour response to established and trial therapies.

Monoclonal antibody Ki-67: its use in histopathology.

Detection of the chromosomal translocation t(11;14) by polymerase chain reaction in mantle cell lymphomas.

Dysmyelopoietic syndromes cover sideroblastic or nonsideroblastic refractory anemia with or without excess of blasts, subacute or chronic myelomonocytic leukemia. The evolution of 193 patients was studied with regard to the initial hematologic picture. A certain number of variables of prognostic value have then been isolated: excess of marrow blasts (more than 5%); presence of circulating blasts or karyotypic anomalies; reduction in the number of polymorphonuclear leukocytes (less than 1.043 lo9/ I), of monocytes (less than 0.136 109/1), of platelets (less than 140 109/1), of in vitro granulopoietic progenitors (less than 5 per 10' nucleated cells plated), of erythrocytic incorporation of '9Fe at day 14 (less than 12%), of hemoglobin level (less than 92 g/l); previous exposure to radiation or chemotherapy; early hemolysis in SICr-labeled erythrocytes study; marrow heterogeneity in histology; less than 20% of ringed sideroblasts. The correlation between these variables and adjustements related to the length of survival and the order of magnitude of the critical level of the log-rank test show that the most significant variables in descending order are: excess of marrow blasts, neutropenia, thrombopenia, presence of circulating blasts, the type of erythropoietic insufficiency, and decrease of in vitro growth. Cancer 52:83-90, 1983. EMOPOIETIC DYSPLASIAS or dysmyelopoietic synH dromes (DMPS)1*2 correspond to several morphological entities which are characterized by the presence of one or several cytopenias and marrow maturation abnormalities. Evolution occurs progressively, leading to an aggravation of cytopenia and, in a varying percentage of cases, to the appearance of a condition similar to acute leukemia (AL). The occurrence of AL is not obligatory and the date of occurrence, in relation to the onset of the disease, varies considerably. In the absence of transformation into AL, evolution can be prolonged, with death occuring due to an intercurrent disease, or infectious or hemorrhagic complications of the cytopenia. According to the importance of the different anomalies of the blood and marrow, DMPS cases have been described as idiopathic sideroblastic anemia (SA),3,4 refractory anemia with an excess of blasts oli

https://acsjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/1097-0142%2819830701%2952%3A1%3C83%3A%3AAID-CNCR2820520117%3E3.0.CO%3B2-9

Dysmyelopoietic syndromes. A search for prognostic factors in 193 patients.

Glucocorticoids induce G1 as well as S-phase lengthening in normal human stimulated lymphocytes: differential effects on cell cycle regulatory proteins.

Cyclin kinase sub-units (CKS) are known to interact with cyclin-dependent kinases (CDKs), but their functions are not completely understood and their expression in human tissues is not documented. For analyzing relationships of CKS with cell proliferation and/or with differentiation, we investigated the expression of ckshs1 and ckshs2 in normal and malignant human lymphoid cells. ckshs1 and ckshs2 expression appeared to be related to cell proliferation: (i) mRNAs increased with stimulation of normal peripheral-blood lymphocytes, and from the G1 to the SG2M phase in elutriated cells; (ii) P9 proteins were also induced by lymphocyte stimulation and were localized in nucleus where phosphorylated forms of CDK1 were also found; (iii) in vitro, the phosphorylated forms of CDK1 and CDK2 were preferentially linked to CKS. Among 45 patients presenting acute or chronic lymphoid malignancy, ckshs1 and ckshs2 mRNAs varied in a similar way and were significantly correlated to cell proliferation (p < 0.0001). When analysis was restricted solely to acute lymphoblastic leukemia (ALL) this correlation was still found and ckshs1 and ckshs2 were significantly more expressed in T-cell ALL than in B-cell-lineage ALL. These results confirm relationships between ckshs expression and cell proliferation, and pose the question of a link with cell differentiation.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/%28SICI%291097-0215%2819990702%2982%3A1%3C98%3A%3AAID-IJC17%3E3.0.CO%3B2-A

ckshs expression is linked to cell proliferation in normal and malignant human lymphoid cells.

Simultaneous analysis of DNA and cellular proteins provides information on cell proliferation and metabolism. Cellular protein content coupled with nuclear geometric parameters can be used to evaluate cellular maturation and differentiation. In this study, leucoblasts from 50 cases of adult acute myeloid leukemia were analyzed by flow cytometry, and semiautomatic morphometry was performed on bone marrow smears. Ethanol-fixed bone marrow blast cells were stained for DNA with propidium iodide (PI) and for proteins with fluorescein isothiocyanate (FITC). On the resulting FITC versus PI histograms we defined the cells with low protein content which are associated with a nonproliferating subpopulation (LPC fraction). Low protein content fraction and S-phase are correlated (p less than 0.01). The LPC fraction values are more dispersed than S-phase values and thus should indicate more clearly eventual differences between cellular populations. This hypothesis has been tested with the prognostic significance of cell-cycle variables: The LPC fraction was significantly higher in the complete remission group than in the other (p less than 0.01), while S-phase did not show any difference. The peak value of the protein content histograms is significantly lower in the granulocytic leukemias (M1, M2, M3) than in the leukemias with a monoblastic component (M4, M5). Furthermore, we showed that the differentiation and the maturation of the myeloid blast cells modify the nuclear size. The combination of these two parameters provides useful information for cytological classification.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/cyto.990060109

Paul André Bryon

Papers

Detection of the chromosomal translocation t(11;14) by polymerase chain reaction in mantle cell lymphomas.

Dysmyelopoietic syndromes. A search for prognostic factors in 193 patients.

Glucocorticoids induce G1 as well as S-phase lengthening in normal human stimulated lymphocytes: differential effects on cell cycle regulatory proteins.

ckshs expression is linked to cell proliferation in normal and malignant human lymphoid cells.

Cell-cycle, protein content, and nuclear size in acute myeloid leukemia.