ABSTRACT
Hyperdiploid and non-hyperdiploid multiple myeloma represents distinct biological entities characterized by different patterns of genetic changes. We sought to determine whether ploidy category (non-hyperdiploid versus hyperdiploid) remains stable over time from diagnosis to progression. Of the 43 patients studied (39 by flow cytometry DNA index and 4 by a FISH-based index), only five (12%) altered their ploidy status at progression. In three of these patients, the change may possibly be attributable to technical artifacts because of the low absolute change in DNA index. For those who retain their ploidy subtypes, the DNA index change minimally (3.75+/-4.87%). It would appear that the initiating genetic events underlying hyperdiploid and non-hyperdiploid MM that marks them out as distinct entities continue to dominate and persist during disease evolution and progression.
Subject(s)
DNA, Neoplasm/genetics , Multiple Myeloma/genetics , Ploidies , DNA, Neoplasm/analysis , Disease Progression , Female , Flow Cytometry , Humans , In Situ Hybridization, Fluorescence , Male , Multiple Myeloma/pathologyABSTRACT
The nonrandom recurrent nature of chromosome abnormalities in myeloma suggests a role for them in disease pathogenesis. We performed a careful cytogenetic analysis of patients with abnormal karyotypes (n = 254), to discern patterns of association, search for novel abnormalities and elucidate clinical implications. Patients with karyotypic abnormalities suggestive of myelodysplasia/acute leukemia were excluded. In this study we compared survival by abnormality only between patients with abnormal karyotypes. Patients with abnormalities were more likely to have features of aggressive disease as compared to all other patients without abnormalities entered into the myeloma database (lower hemoglobin, higher beta(2)-microglobulin, labeling-index and plasmocytosis; all P < 0.0001). Several groups of patients could be readily identified; hypodiploid (22%), pseudodiploid (36%), hyperdiploid (31%) and near-tetraploid (11%). Clustering associations were seen among several trisomies and monosomy of chromosome 13 and 14. Several monosomies (-2, -3, -13, -14 and -19), 1p translocations/ deletions, and hypodiploidy were associated with a significantly shorter survival. Trisomy of chromosome 13 was rare ( <2%). Even among patients with abnormal karyotypes, specific chromosome abnormalities can impart biologic variability in myeloma, including several monosomies, hypodiploidy and abnormalities of 1p.
Subject(s)
Chromosome Aberrations , Multiple Myeloma/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Chromosome Mapping , Cluster Analysis , Cytogenetics/methods , Databases, Factual , Female , Humans , Male , Middle Aged , Multiple Myeloma/mortality , Prognosis , Racial Groups , Survival Analysis , Time Factors , Trisomy , United StatesABSTRACT
Inflammatory cells are involved in the pathogenesis of tissue injury through release of cytokines and biologically active compounds. This study used a novel, noninvasive method to assess the association between granulocyte transmigration and structural and molecular changes in radiation enteropathy. A 4 cm loop of rat small intestine was exposed to 0, 2.8, 12, or 23 Gy localized irradiation. Feces was collected in metabolic cages before and 3, 7, 14, 28, and 42 days after irradiation. Granulocyte marker protein (GMP) was measured in buffer extracts of feces by enzyme-linked immunosorbent assay (ELISA). Irradiated and shielded intestine were procured at 2 and 26 weeks and assessed for histopathologic injury [radiation injury score (RIS)], ED-2 positive macrophages, and interleukin-1 alpha (IL-1 alpha) positive cells. Irradiated intestine exhibited characteristic histopathologic alterations and increased numbers of macrophages and IL-1 alpha positive cells. There was a highly significant dose-dependent increase in post-radiation GMP (P < 0.0001). Maximal GMP excretion occurred 3-7 days after irradiation. Six weeks after irradiation, GMP excretion had returned to normal in the 2.8 and 12 Gy groups, but was still 3.5 times higher in the 23 Gy group than in controls. The associations between early GMP excretion and RIS and fibrosis at 26 weeks were highly significant (P < 0.001 and P < 0.0001, respectively). Post-radiation granulocyte transmigration is dose-dependent and correlates with structural and molecular changes, as well as with subsequent chronic injury. The GMP assay is a sensitive, non-invasive indicator of acute intestinal radiation injury and a promising biological predictor of chronic toxicity. Our data underscore the importance of consequential mechanisms in radiation enteropathy.
