Development of a Patient-Reported Outcomes Measurement Information System (PROMIS®) short form for measuring physical function in geriatric rehabilitation patients.

PURPOSE: To develop and test the validity of a Patient-Reported Outcomes Measurement Information System (PROMIS®) short form for measuring physical function of geriatric rehabilitation patients. METHODS: Experts selected items from the Dutch-Flemish PROMIS v1.2 Physical Function (PROMIS-PF) item bank and proposed new items to develop the PROMIS-PF short form for geriatric rehabilitation (PROMIS-PF-GR). Patients evaluated its content validity. Structural validity was assessed by evaluating unidimensionality (confirmatory, exploratory, and bi-factor analyses [criterion: Omega H > 0.80 and ECV > 0.60]), local independence (criterion: residual correlation < 0.20) ,and monotonicity (criterion: Hi-coefficient ≥ 0.30). Measurement invariance was assessed by evaluating Differential Item Functioning (DIF) between geriatric rehabilitation patients and people from the general population using ordinal logistic regression. Internal consistency was assessed by calculating Cronbach's alpha (criterion: alpha ≥ 0.70). RESULTS: Experts selected 24 items from the PROMIS-PF item bank and proposed one new item which was not included in the short form. Patients considered the 24 items relevant and containing essential information. The PROMIS-PF-GR's psychometric properties were evaluated in 207 patients (mean age ± SD, 80.0 ± 8.3 year; 58% female). The 24 items were found to be sufficiently unidimensional (Omega H = 0.82, ECV = 0.70), locally independent (98.7% item pairs), and monotone (all ≥ 0.32). Five items were flagged for DIF, but their impact on the total score was negligible. Cronbach's alpha was 0.94. CONCLUSION: The PROMIS-PF-GR was developed from the PROMIS-PF and has good content validity, structural validity, measurement invariance, and internal consistency in Dutch geriatric rehabilitation patients. We recommend to confirm the content validity of the PROMIS-PF-GR in other countries.

HBx triggers either cellular senescence or cell proliferation depending on cellular phenotype.

Replicative senescence is a hallmark of chronic liver diseases including chronic hepatitis B virus (HBV) infection, whereas HBV-encoded oncoproteins HBx and preS2 have been found to overcome senescence. HBx possesses a C-terminal truncation mainly in hepatocellular carcinomas but also in noncancerous liver tissues. Here, by cell counting, BrdU incorporation, MTT proliferation assay, cell cycle analysis, SA-ßgal staining and Western blotting in primary and malignant cells, we investigated the effect of HBx C-terminal mutants on cellular senescence. HBx C-terminal mutants were found to trigger cellular senescence in primary MRC5 cells, and malignant liver cells Huh7, and SK-Hep1. In contrast, these mutants promoted the proliferation of HepG2 malignant liver cells. The pro-senescent effect of HBx relied on an increased p16(INK4a) and p21(Waf1/Cip1) expression, and a decreased phosphorylation of Rb. Together, these results suggest that the two main variants of HBx present in HBV-infected liver possess opposite effects on cellular senescence that depend on the phenotype of infected cells.

Assessment of volumetric changes with a best-fit method in three-dimensional stereophotograms.

OBJECTIVE: Different three-dimensional stereophotogrammetry systems and analyzing methods exist that often use landmarks for comparison. Measurement errors in landmark or surface comparison are mostly within 1 mm, which seems clinically acceptable. The aim of this study was to validate a three-dimensional stereophotogrammetric best-fit method of assessing volumetric changes and to compare three devices. METHODS: The validation of the best-fit method was at first done on a life-size dummy head. Scans were made in the ideal position, as well as in four additional positions, and a scan was made in which a soft putty specimen was added to the dummy head. The comparison was executed with a best-fit method using triangulation. Student's t tests were used to detect statistically significant differences. Second, comparisons were made among scans of a white man in the ideal position and with volume changes added. RESULTS: The different positions tested for the dummy head showed no significant volume differences within each system or among systems. The differences found when adding a soft putty specimen fell into the same range as the differences between various positions. The differences within a live situation were 10 times greater compared with the dummy-head situation. CONCLUSIONS: In a dummy-head situation, the different systems gave similar results when tested with a best-fit method. However, in live situations the differences may become 10 times greater, possibly due to different facial expressions. These differences may become clinically relevant and, therefore, further research in volumetric changes is needed.

Somatic mutation in human T-cell leukemia virus type 1 provirus and flanking cellular sequences during clonal expansion in vivo.

BACKGROUND: Human T-cell leukemia virus type 1 (HTLV-1), the causative agent of adult T-cell leukemia/lymphoma, shows intrapatient genetic variability. Although HTLV-1 can replicate via the reverse transcription of virion RNA to a double-stranded DNA provirus (the conventional manner for retroviruses), its predominant mode of replication is via the clonal expansion (mitosis) of the infected cell. This expansion is achieved by the viral oncoprotein Tax, which keeps the infected CD4 T lymphocyte cycling. Because Tax also interferes with cellular DNA repair pathways, we investigated whether somatic mutations of the provirus that occur during the division of infected cells could account for HTLV-1 genetic variability. METHODS: An inverse polymerase chain reaction strategy was designed to distinguish somatic mutations from reverse transcription-associated substitutions. This strategy allows the proviral sequences to be isolated together with flanking cellular sequences. Using this method, we sequenced 208 HTLV-1 provirus 3' segments, together with their integration sites, belonging to 29 distinct circulating cellular clones from infected individuals. RESULTS: For 60% of the clones, 8%-80% of infected cells harbored a mutated HTLV-1 provirus, without evidence of reverse transcription-associated mutations. Mutations within flanking cellular sequences were also identified at a frequency of 2.8 x 10(-4) substitution per base pair. Some of these clones carried multiple discrete substitutions or deletions, indicating progressive accumulation of mutations during clonal expansion. The overall frequency of somatic mutations increased with the degree of proliferation of infected T cells. CONCLUSIONS: These data indicate that, in vivo, HTLV-1 variation results mainly from postintegration events that consist of somatic mutations of the proviral sequence occurring during clonal expansion. The finding of substitutions in flanking sequences suggests that somatic mutations occurring after integration, presumably coupled with selection, help move the cellular clones toward a transformed phenotype, of which adult T-cell leukemia/lymphoma is the end point.

Pharmacokinetics of 5-fluorouracil assessed with a sensitive mass spectrometric method in patients on a dose escalation schedule.

The pharmacokinetics of 5-fluorouracil (5-FUra) was investigated in 21 patients with advanced cancer (mainly colorectal cancer). 5-FUra was administered as weekly i.v. bolus injections usually at a starting dose of 500 mg/m2. Every 4 weeks the dose was escalated by 20% until dose-limiting toxicity was observed. Whenever possible, pharmacokinetic studies were performed at dose escalation. 5-FUra plasma concentrations were measured by high pressure liquid chromatography and a sensitive gas chromatography-mass spectrometry assay with a sensitivity as low as 3 x 10(-9) M. According to the 42 plasma concentration versus time curves, in all but one of the patients total body clearance decreased with increasing 5-FUra doses, consistent with the nonlinear pharmacokinetics of 5-FUra. The ultrasensitive assay revealed an almost horizontal phase in the plasma concentration versus time curves at plasma concentrations of 10(-8) to 10(-9) M. This plateau did not show correlation with the area under those curves. The use of a logistic regression method showed that clinical toxicity was correlated with the area under the plasma concentration versus time curve of 5-FUra.

Lenalidomide with or without erythropoietin in transfusion-dependent erythropoiesis-stimulating agent-refractory lower-risk MDS without 5q deletion.

After failure of erythropoiesis-stimulating agents (ESAs), lenalidomide (LEN) yields red blood cell (RBC) transfusion independence (TI) in 20-30% of lower-risk non-del5q myelodysplastic syndrome (MDS). Several observations suggest an additive effect of ESA and LEN in this situation. We performed a randomized phase III study in 131 RBC transfusion-dependent (TD, median transfusion requirement six RBC units per 8 weeks) lower-risk ESA-refractory non-del5q MDS. Patients received LEN alone, 10 mg per day, 21 days per 4 weeks (L arm) or LEN (same schedule) + erythropoietin (EPO) beta, 60,000 U per week (LE arm). In an intent-to-treat (ITT) analysis, erythroid response (HI-E, IWG 2006 criteria) after four treatment cycles (primary end point) was 23.1% (95% CI 13.5-35.2) in the L arm and 39.4% (95% CI 27.6-52.2) in the LE arm (P=0.044), while RBC-TI was reached in 13.8 and 24.2% of the patients in the L and LE arms, respectively (P=0.13). Median response duration was 18.1 and 15.1 months in the L and LE arms, respectively (P=0.47). Side effects were moderate and similar in the two arms. Low baseline serum EPO level and a G polymorphism of CRBN gene predicted HI-E. Combining LEN and EPO significantly improves erythroid response over LEN alone in lower-risk non-del5q MDS patients with anemia resistant to ESA.

Proliferation of HTLV-1 infected circulating cells in vivo in all asymptomatic carriers and patients with TSP/HAM.

Assuming that the clonal expansion of T cells harbouring the human T-cell leukemia virus type 1 (HTLV-1) provirus is a central feature of HTLV-1 infection, the identification of such cells was sought among a series of 19 asymptomatic carriers and 19 cases of tropical spastic paraparesis/HTLV-1 associated myelopathy (TSP/HAM) devoid of malignancy. Two PCR based protocols designed to amplify the host cell-HTLV-1 proviral integration sites were used. In all cases large numbers of proliferating clones could be identified. The proportion of some clones was > 1/1500 peripheral blood mononuclear cells (PBMCs) with the suggestion that their number increased as a function of age among asymptomatic carriers.

Persistent oligoclonal expansion of human T-cell leukemia virus type 1-infected circulating cells in patients with Tropical spastic paraparesis/HTLV-1 associated myelopathy.

The pattern of HTLV-1 replication was assessed through PCR amplification of the 3' proviral integration sites in patients with TSP/HAM at different times. Integration sites were sequenced and oligonucleotides specific for the flanking sequences were synthesized. Together with HTLV-1 LTR specific primers, clonotypic nested PCR was performed on peripheral blood from two patients. The frequencies of five clones studied ranged from 1/300 to 1/1500 PBMCs while four clones persisted for more than 1-5 years. It would seem that Tax driven expansion of T cells may persist for considerable periods of time in TSP/HAM despite strong cellular immunity. This may provide a background for the accumulation of subsequent mutations leading to malignancy.

High circulating proviral load with oligoclonal expansion of HTLV-1 bearing T cells in HTLV-1 carriers with strongyloidiasis.

Adult T cell leukemia (ATLL) develops in 3 - 5% of HTLV-1 carriers after a long period of latency during which a persistent polyclonal expansion of HTLV-1 infected lymphocytes is observed in all individuals. This incubation period is significantly shortened in HTLV-1 carrier with Strongyloides stercoralis (Ss) infection, suggesting that Ss could be a cofactor of ATLL. As an increased T cell proliferation at the asymptomatic stage of HTLV-1 infection could increase the risk of malignant transformation, the effect of Ss infection on infected T lymphocytes was assessed in vivo in HTLV-1 asymptomatic carriers. After real-time quantitative PCR, the mean circulating HTLV-1 proviral load was more than five times higher in HTLV-1 carriers with strongyloidiasis than in HTLV-1+ individuals without Ss infection (P<0.009). This increased proviral load was found to result from the extensive proliferation of a restricted number of infected clones, i.e. from oligoclonal expansion, as evidenced by the semiquantitative amplification of HTLV-1 flanking sequences. The positive effect of Ss on clonal expansion was reversible under effective treatment of strongyloidiasis in one patient with parasitological cure whereas no significant modification of the HTLV-1 replication pattern was observed in an additional case with strongyloidiasis treatment failure. Therefore, Ss stimulates the oligoclonal proliferation of HTLV-1 infected cells in HTLV-1 asymptomatic carriers in vivo. This is thought to account for the shortened period of latency observed in ATLL patients with strongyloidiasis. Oncogene (2000) 19, 4954 - 4960

Clinical significance of p53 mutations in newly diagnosed Burkitt's lymphoma and acute lymphoblastic leukemia: a report of 48 cases.

PURPOSE: To correlate the presence of p53 mutations and initial characteristics, response to chemotherapy, and survival in newly diagnosed Burkitt's lymphoma (BL) and Burkitt's acute lymphoblastic leukemia (L3 ALL). PATIENTS AND METHODS: Forty-eight patients with newly diagnosed BL or L3 ALL, most of whom were treated with very intensive regimens, including early CNS disease treatment, were studied. Detection of p53 mutations was made by single-strand conformation polymorphism (SSCP) analysis of exons 5 to 8 of the gene, and mutations were determined by direct sequencing of exons with abnormal SSCP findings. Comparison of outcome between mutated and nonmutated cases was made in all patients and also after excluding five patients who received therapeutic regimens considered as suboptimal and one patient who died of AIDS while in complete remission (CR), as those six patients had no p53 mutations. RESULTS: A point mutation was found in nine patients (19%), and consisted of a missense mutation in seven and a chain-terminating mutation in two. SSCP, sequence, and cytogenetic analysis strongly suggested that eight of nine patients with mutations had retained the normal p53 allele, which had been lost in the remaining patient. These findings were confirmed by fluorescence-in-situ hybridization (FISH) with a p53-specific probe in two patients, including the one who had lost the normal p53 allele. Unexpectedly, mutations were significantly less frequent in patients with disseminated disease, ie, L3 ALL or stage IV BL (four of 35, 11%), than in more localized forms, ie, BL stage I, II, or III (five of 13, 38%) (P = .03). CR rates were similar in mutated (78%) and nonmutated cases (78%). The actuarial disease-free interval (DFI) after 12 months and actuarial survival rates after 24 months were 49% and 66%, respectively, in patients with mutations, and 73% and 48%, respectively, those without mutations. The differences were not significant. CONCLUSION: Our findings suggest that, contrary to what is seen in most other neoplasias, p53 mutations in newly diagnosed BL and L3 ALL are not associated with extensive tumor mass or poor response to intensive therapeutic regimens. It is hypothesized that this difference with most tumors could be due to the fact that p53 mutations in BL and L3 ALL are generally associated with persistence of a normal residual p53 allele, contrary to what is observed in the majority of tumors.

Allogeneic bone marrow transplantation for therapy-related myelodysplastic syndrome and acute myeloid leukemia: a long-term study of 70 patients-report of the French society of bone marrow transplantation.

PURPOSE: To identify predictive factors of survival, relapse, and transplantation-related mortality (TRM) among patients with therapy-related myelodysplastic syndrome (t-MDS) or acute leukemia (t-AML) who underwent allogeneic bone marrow transplantation (BMT). PATIENTS AND METHODS: From 1980 to 1998, 70 patients underwent allogeneic BMT for t-MDS (n = 31) or t-AML (n = 39) after prior cytotoxic exposure. Thirty-three patients had received induction-type chemotherapy before BMT. At the time of transplantation, there were 24 patients in complete remission (CR) and 46 with active disease. RESULTS: With a median follow-up of 7.9 years (range, 1.1 to 18.8 years) after BMT, 16 patients are alive, whereas 19 died of relapse, 34 of TRM, and one of relapse of the primary disease. The estimated 2-year overall survival, event-free survival, relapse, and TRM rates were 30% (95% confidence interval [CI], 19% to 40%), 28% (95% CI, 18% to 39%), 42% (95% CI, 26% to 57%), and 49% (95% CI, 36% to 62%), respectively. In multivariable analysis, age greater than 37 years, male sex, positive recipient cytomegalovirus (CMV) serology, absence of CR at BMT, and intensive schedules used for conditioning were associated with poor outcome. CONCLUSION: BMT is an effective treatment for patients with t-MDS or t-AML who have responsive disease and, in particular, who have no poor-risk cytogenetic features. The poor results of the other patients, especially those with active disease at BMT, emphasize the need to delineate indications and perform prospective protocols.

Molecular and cellular aspects of HTLV-1 associated leukemogenesis in vivo.

Most cancers and leukemias are preceded by a prolonged period of clinical latency during which cellular, chromosomal and molecular aberrations help move normal cell towards the malignant phenotype. The problem is that premalignant cells are usually indistinguishable from their normal counterparts, thereby ruling out the possibility to investigate the events that govern early leukemogenesis in vivo. Adult T cell leukemia/lymphoma (ATLL) is a T cell malignancy that occurs after a 40-60-year period of clinical latency in about 3-5% of HTLV-1-infected individuals. ATLL cells are monoclonally expanded and harbor an integrated provirus. A persistent oligo/polyclonal expansion of HTLV-1-bearing cells has been shown to precede ATLL, supporting the fact that in ATLL tumor cells arise from a clonally expanding non-malignant cell. It is possible to isolate infected, ie preleukemic, cells during the premalignant asymptomatic phase of the infection, thus providing an exceptional system to study the mechanisms underlying human cancers. Here we review some of the consequences of HTLV-1 on its host cell in vivo, at different stages of infection.

Association of myelodysplastic syndrome and relapsing polychondritis: further evidence.

We report five patients with both a myelodysplastic syndrome (MDS) and relapsing polychondritis (RP), that represented 0.6% of all MDS and 28% of all RP diagnosed over a period of 14 years. Ten other cases had previously been reported (four in detail), supporting a non-fortuitous association between the two disorders, already suggested for MDS and some other immunological disorders.

Differential efficacy of adenoviral mediated gene transfer into cells from hematological cell lines and fresh hematological malignancies.

As a first step to evaluate the possibility of gene therapy using adenoviral vectors in hematological malignancies in vivo, we tested the efficacy of gene transfer by a recombinant adenovirus in cell lines and fresh cells from various hematological neoplasms. Thirteen cell lines and samples from 27 patients were studied. Cells were infected by a recombinant adenovirus expressing beta galactosidase gene (Ad RSV betagal) and efficacy of transduction assessed by evaluating betagal expression in cells with a histochemical method. After infection of the cells at a multiplicity of infection (MOI) of 200 p.f.u./cell, the percentage of beta gal-positive cells after 48h was high in two cell lines. K562 (64%) and RPMI 8226 (a myeloma cell line, 65%), relatively large in the two myeloma cell lines tested (41% and 20%, respectively) and in MT4 (an adult T cell leukemia cell line, 38%) and low or absent in other cell lines. In fresh samples from AML, ALL, CLL, NHL, myeloma and MDS, no betagal positive cells were seen 48h and 72h after infection, except in one case of myeloma and one case of CLL (where 10% and 2% of betagal positive cells were seen after infection, respectively). Exposure of fresh malignant cells to GM-CSF before and during adenoviral infection, in three cases, did not increase the number of transfected cells. This suggests that adenoviral vectors, at least in their present form, cannot efficiently be used for direct gene transfer in hematological malignant cells.

All-trans retinoic acid in adult chronic myelomonocytic leukemia: results of a pilot study.

Retinoids can inhibit the spontaneous in vitro growth of CFU-GM observed in juvenile chronic myeloid leukemia (JCML) and, when administered in vivo, have shown some clinical benefit in this disease. Because adult chronic myelomonocytic leukemia (CMML) has many features in common with JCML, we treated 10 cases of advanced adult CMML with ATRA (45 mg/m2/day). Five of them were also tested in vitro. After two patients had a rapid increase in WBC counts and clinical signs reminiscent of the 'ATRA syndrome' seen in acute promyelocytic leukemia, with fatal outcome in one of them, it was decided to add hydroxyurea (HY) to ATRA to patients with high WBC at inclusion or during ATRA treatment, and no more cases of ATRA syndrome were seen. Overall, six patients received ATRA + HY and four ATRA alone. Four patients had a minor but significant response with reduction of transfusion requirement (two cases) or increase in platelet counts (two cases). Apart from the ATRA syndrome, no other side-effect of ATRA was seen. Bone marrow mononuclear cells showed spontaneous growth of CFU-C in methylcellulose in the five patients tested in vitro, with a predominance of CFU-M. ATRA (10(-7) M) inhibited CFU-M growth in all cases, but increased CFU-G growth in one patient who developed the ATRA syndrome. No differentiation of bone marrow myeloid cells after short-term liquid culture with ATRA was observed. A decrease of CFU-C growth was observed in the four patients reevaluated during follow-up. In some cases of CMML, ATRA can improve anemia or thrombocytopenia but not other parameters. Furthermore, it can also induce hyperleukocytosis and ATRA syndrome in some patients, requiring the rapid addition of cytoreductive agents such as HY.

Treatment with very low-dose GM-CSF in myelodysplastic syndromes with neutropenia. A report on 28 cases.

We treated 28 cases of myelodysplastic syndrome (MDS) with neutropenia by very low-dose GM-CSF (0.25 or 0.5 micrograms/kg/day). Median age was 69 years. Nine patients had RA, 18 had RAEB, and one had RARS. Eighteen patients had absolute neutrophil counts (ANC) < or = 0.5 x 10(9)/l, and ten had ANC between 0.5 and 1.0 x 10(9)/l. Ten patients had experienced > or = WHO grade II infection(s) during the preceding 3 months. Eighteen patients (64%) had a response (i.e. ANC at least doubled and > or = 1 x 10(9)/l after 1 month), including 4/8 patients treated at 0.25 mu/kg/day, and 14/20 treated at 0.5 microgram/kg/day (difference not significant). Two of the non-responders obtained a response after dose escalation to 0.5 and 1 microgram/kg/day, respectively. The only prognostic factor of response was FAB subtype (10/11 responses in patients with RA or RARS, vs. 8/17 in RAEB, p = 0.04). Patients with ANC < or = 0.5 x 10(9)/l had a 55% (10/18) response rate, which was not significantly lower than the 80% (8/10) response rate observed in patients with ANC > 0.5 x 10(9)/l. Side-effects were generally moderate, except in three patients where the drug had to be discontinued, including the only patient who progressed to AML. In responders, GM-CSF was continued during 2 to 14 months (median 6), and the response persisted in all but one case, who relapsed after 60 days of treatment. During follow-up, only one responder had > or = WHO grade II infections, as compared to five of the non-responders (of whom two had fatal infectious episodes). In conclusion, very low-dose GM-CSF can durably increase ANC in about two thirds of MDS with neutropenia. Although it remains to be shown in randomized trials that it can reduce the incidence of infections and improve survival in MDS, very low-dose GM-CSF may be an interesting approach in MDS, associated to reasonable cost.

Absence of amplification of MDM2 gene, a regulator of p53 function, in myelodysplastic syndromes.

The MDM2 gene is a gene whose product binds to p53 and regulates its function. Amplification of MDM2 has been found in human sarcomas, where it leads to inactivation of p53. In 64 cases of generally advanced myelodysplastic syndromes, we found no amplification or rearrangement of MDM2 gene by Southern analysis. MDM2 RNA was also normal in the 15 cases where Northern analysis was made. Thus, amplification of MDM2 is not seen or must be very rare in myelodysplastic syndrome (MDS). Because P53 gene mutations are not frequent in MDS, inactivation of p53 seems to be, overall, a rare pathogenetic event in MDS.

Expression of the multidrug resistance P glycoprotein in newly diagnosed adult acute lymphoblastic leukemia: absence of correlation with response to treatment.

We analyzed P glycoprotein (PGP) expression and its correlation with hematological parameters and outcome in 50 cases of newly diagnosed adult acute lymphoblastic leukemia (ALL). PGP expression was evaluated by flow cytometry using MRK16 monoclonal antibody (MoAb) and/or immunocytochemistry on marrow slides, using JSB1 MoAb. Thirty-two of the 50 patients (64%) were PGP positive by at least one of the two methods, which gave concordant results in 15 of the 18 cases in which they were both used. No correlation between PGP expression and clinical and hematological parameters including WBC counts, immunophenotype and karyotype was seen, although there was a trend for more frequent CD34 expression in PGP-positive cases. All patients were treated with intensive chemotherapy. We found no difference in complete remission (CR) rate, actuarial disease-free survival and survival in PGP-positive and PGP-negative cases. Our findings suggest that the clinical significance of PGP expression is less clear in ALL than in AML. Wider use of functional techniques of evaluation of mdr1 gene expression, which assess the 'pumping' activity of PGP, and their correlation with quantitative analysis of mdr1 mRNA and protein, would probably improve knowledge of the role of PGP in ALL. Analysis of other mechanisms of drug resistance, especially multidrug resistance-associated protein (MRP) expression, would also be useful.

Myelodysplastic syndromes and acute myeloid leukemia with 17p deletion. An entity characterized by specific dysgranulopoïesis and a high incidence of P53 mutations.

We looked for correlations between cytogenetic rearrangements leading to 17p deletion and presence of dysgranulopoïesis and p53 mutations in MDS and AML. Forty-nine (4.3%) of the MDS and AML studied cytogenetically at our institution over a period of 11 years had detectable 17p deletion, through monosomy 17 (14 cases) or rearrangements of chromosome 17 (generally unbalanced translocations between 17p and another chromosome) (35 cases). Most of the patients had additional complex cytogenetic findings, and 10 cases were therapy related. In 70% of the patients with 17p deletion, a particular type of dysgranulopoïesis, combining pseudo-Pelger-Huët anomaly and small vacuolated neutrophils was seen in > 5% marrow neutrophils, whereas 69% of the patients had a p53 mutation, generally in a missense mutation involving exons 5 to 8 of the p53 gene. FISH analysis, performed in eight cases, confirmed loss of one P53 allele in all of them. No DNA fragmentation suggesting increased apoptosis was found in marrow samples. Response to chemotherapy was almost uniformly poor and median survival was only 3 months. Analysis of dysgranulopoïesis and p53 mutations were also made in 'control' groups of MDS and AML without 17p deletion. 'Typical' dysgranulopoïesis, combining pseudo-Pelger-Huët anomaly and small vacuolated neutrophils in > 5% marrow neutrophils, was not seen in any of the 47 MDS and AML without 17p deletion analyzed and without p53 mutation (P = 10(-4) with patients having 17p deletion), and was seen in one of five patients without 17p deletion but with a p53 mutation. Only 3.1% of 256 MDS and AML without 17p deletion had a p53 mutation (P = 10(-4) with patients having 17p deletion). These findings suggest that 17p deletion, in MDS and AML, is strongly correlated to the presence of a particular type of dysgranulopoïesis and to a high incidence of p53 mutations, and that MDS and AML with 17p deletion could constitute a new morphological-cytogenetic-molecular entity in myeloid disorders.

Cytogenetic analysis has strong independent prognostic value in de novo myelodysplastic syndromes and can be incorporated in a new scoring system: a report on 408 cases.

Although the prognostic value of cytogenetic analysis has previously been demonstrated in myelodysplastic syndromes (MDS), karyotype had not been included in previously published scoring systems, such as Bournemouth and Sanz's scores. We studied karyotype at diagnosis in 408 cases of de novo MDS (after excluding therapy-related MDS). Karyotypes were classified in 10 groups: normal; isolated del 5q; del 5q and other rearrangements; isolated +8; isolated -7 or del 7q; del 20q; isolated -Y; miscellaneous single rearrangements; -7 or del 7q and other rearrangements; miscellaneous complex rearrangements. Karyotypes were considered complex when at least three chromosomes were rearranged. Complex karyotypes included all patients with del 5q and other rearrangements, -7 or del 7q and other rearrangements, and miscellaneous complex rearrangements (i.e. three of the 10 groups). Median actuarial survival of the 408 patients was 28 months, and 90 patients (22%) progressed to acute myeloid leukemia (AML). For survival, bone marrow (BM) blasts, circulating blasts, white blood cell (WBC), neutrophil count, platelet count, hemoglobin, age, sex, FAB classification, and Bournemouth and Sanz's scores had strong prognostic value. Cytogenetics also had strong prognostic value. An unfavorable cytogenetic group (patients with complex karyotypes) was identified. On the other hand, although patients with isolated del 20q and del 5q had a somewhat better prognosis than other patients with non-complex cytogenetic findings, they could not be statistically individualized as a favorable group, possibly owing to their relatively limited number. By multivariate regression analysis, a three-variable new scoring system could be designed based on karyotype (1 point for complex karyotype; 0 for other groups), platelets (0 for > 75 x 10(9)/l; 1 for < 75 x 10(9)/l), and BM blasts (0 for < 5%, 1 for 5-10%, 2 for > 10%). The total score (addition of points for the three variables) was able to separate patients in three groups with low (score 0) intermediate (score 1 or 2), and high risk (score 3 or 4) which included 34%, 47%, and 19% of the patients, and had a median survival of 55, 24, and 6 months, respectively (chi 2 = 110, p < 10(-4)). This new score (Lille score) was able to subdivide risk groups according to Bournemouth and Sanz's scores into further subgroups of different prognoses. For progression to AML, BM blasts, circulating blasts, WBC count, hemoglobin, FAB type, and karyotype had prognostic value by univariate analysis.(ABSTRACT TRUNCATED AT 400 WORDS)