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Biomedical subjects

P G Nilsson

Publications and source records attributed to P G Nilsson.

At least 19 recordsLinked to original sources
PubMed2002

Pooled analysis of clinical and cytogenetic features in treatment-related and de novo adult acute myeloid leukemia and myelodysplastic syndromes based on a consecutive series of 761 patients analyzed 1976-1993 and on 5098 unselected cases reported in the literature 1974-2001.

To ascertain the frequency of treatment-related acute myeloid leukemias and myelodysplastic syndromes (t-AML/t-MDS) in an unselected series, we have identified all adult cases analyzed in our department from 1976 to 1993. Further aims were to compare karyotypic features of t-AML/t-MDS with de novo AML/MDS, in our material as well as in 5098 unselected, cyto- genetically abnormal, published cases, and to analyze associations between type of prior therapy and karyotype. Among our 372 AML and 389 MDS, 47 (13%) were t-AML and 62 (16%) were t-MDS. Clonal abnormalities were significantly more common in t-AML and t-MDS than in de novo disease (68% vs 50%, P < 0.05 and 84% vs 45%, P < 0.001, respectively). Among the available 4230 AML and 1629 MDS (the present series and published cases), 14% were t-AML and 15% were t-MDS. In t-AML/t-MDS, the number of anomalies and the ploidy levels differed significantly from de novo cases, with complex and hypodiploid karyotypes being more common in t-AML/t-MDS. In t-AML, unbalanced changes in general, t(1;3), der(1;7), 3p-, -5, 5q-, -7, 7q-, t(9;11), t(11;19), t(11q23), der(12p), -17, der(17p), -18, and -21 were significantly more frequent than in de novo AML. In t-MDS, -5, -7, 7q-, 13q-, der(17p), and -18 were significantly more common. Type of prior treatment correlated significantly with number of anomalies in t-AML and with ploidy levels in t-AML/t-MDS. The frequencies of several aberrations varied with type of therapy, eg, 5q- was more frequent in radiotherapy-associated t-MDS, monosomy 7 was more common in t-AML and t-MDS after treatment with alkylators, and t(11q23) in t-AML was associated with topoisomerase II inhibitors. Abnormalities significantly more common in de novo disease were +8 as a sole anomaly, balanced changes in general, t(8;21), t(9;22), t(15;17), inv(16), and t(21q22) in AML, and -Y, 5q-, and 20q- as sole anomalies and +8 in MDS. The results emphasize the strong association between previous genotoxic exposure and karyotypic features.

Acute Disease↗
PubMed2001

Paired multiplex reverse-transcriptase polymerase chain reaction (PMRT-PCR) analysis as a rapid and accurate diagnostic tool for the detection of MLL fusion genes in hematologic malignancies.

The MLL gene in chromosome band 11q23 is frequently rearranged in acute lymphoblastic and acute myeloid leukemias. To date, more than 50 different chromosomal regions are known to participate in translocations involving 11q23, many of which affect MLL. The pathogenetically important outcome of these rearrangements is most likely the creation of a fusion gene consisting of the 5' part of the MLL gene and the 3' end of the partner gene. Although abnormalities of the MLL gene as such are generally associated with poor survival, recent data suggest that the prognostic impact varies among the different fusion genes generated. Hence, detection of the specific chimeric gene produced is important for proper prognostication and clinical decision making. We have developed a paired multiplex reverse-transcriptase polymerase chain reaction analysis to facilitate a rapid and accurate detection of the most frequent MLL fusion genes in adult and childhood acute leukemias. To increase the specificity, two sets of primers were designed for each fusion gene, and these paired primer sets were run in parallel in two separate multiplex one-step PCR reactions. Using the described protocol, we were able to amplify successfully, in one single assay, the six clinically relevant fusion genes generated by the t(4;11)(q21;q23) [MLL/AF4], t(6;11)(q27;q23) [MLL/AF6], t(9;11)(p21-22;q23) [MLL/AF9], t(10;11)(p11-13;q23) [MLL/AF10], t(11;19)(q23;p13.1) [MLL/ELL], and t(11;19)(q23; p13.3) [MLL/ENL] in cell lines, as well as in patient material.

Biomarkers, Tumor↗
PubMed2001

The prognostic impact of karyotypic subgroups in myelodysplastic syndromes is strongly modified by sex.

The prognostic impact of karyotypic patterns in a consecutive series of 389 adult myelodysplastic syndromes (MDS) was investigated. Time period did not significantly influence the survival times. In the analyses, the MDS cases were subdivided into the cytogenetic subgroups used in the International Prognostic Scoring System, i.e. favourable [-Y, del(5q) or del(20q) as single aberrations or normal karyotype, n = 241], poor [-7, del(7q), der(1;7) or complex karyotypes, i.e. > or = three abnormalities, n = 89] and intermediate (other aberrations, n = 59). The survival times correlated well with the prognostic subgroups, confirming that the cytogenetic classification was valid. Expressed as hazard ratios (HRs), with the favourable subgroup as the reference, the intermediate and poor subgroup HRs increased to 1.5 (95% confidence interval, 1.1-2.1) and 3.2 (2.4-4.1) respectively. Sex, age, morphological subtype and smoking habits significantly modified this prognostic impact. Shorter survival was detected for men in the favourable and the intermediate subgroups, but not in the poor prognosis subgroup. Using women in the favourable subgroup as the reference and adjusting for age, the HR for men was 1.6 (1.2-2.1) in the favourable subgroup. Adjusting for smoking habits as well decreased the HR to 1.4 (1.1-2.0) and, when also excluding cases with del(5q) as the sole anomaly, no significant difference could be discerned [HR 1.2 (0.9-1.6], suggesting that the better outcome for women in the favourable subgroup was mainly as a result of the '5q-syndrome' and to smoking habits. In the intermediate subgroup, the corresponding HRs were 3.0 (1.5-6.0) when adjusted for age and 2.7 (1.3-5.5) when also adjusted for smoking habits. Different survival times between men and women have never previously been reported for this MDS group. Although it remains to be elucidated whether environmental and/or constitutional factors cause the observed sex-related difference, these observations have obvious clinical ramifications, not least in designing and evaluating therapy protocols.

Adult↗
PubMed2001

Are occupational, hobby, or lifestyle exposures associated with Philadelphia chromosome positive chronic myeloid leukaemia?

OBJECTIVES: To investigate a broad range of occupational, hobby, and lifestyle exposures, suggested as risk factors for Philadelphia chromosome positive (Ph+) chronic myeloid leukaemia (CML). METHODS: A case-control study, comprising 255 Ph+CML patients from southern Sweden and matched controls, was conducted. Individual data on work tasks, hobbies, and lifestyle exposures were obtained by telephone interviews. Occupational hygienists assessed occupational and hobby exposures for each subject individually. Also, occupational titles were obtained from national registries, and group level exposure-that is, the exposure proportion for each occupational title-was assessed with a job exposure matrix. The effects of 11 exposures using individual data and two exposures using group data (organic solvents and animal dust) were estimated. RESULTS: For the individual data on organic solvents, an effect was found for moderate or high intensity of exposure (odds ratio (OR) 3.4, 95% confidence interval (95% CI) 1.1 to 11) and for long duration (15-20 years) of exposure (OR 2.1, 95% CI 1.1 to 4.0). By contrast, the group data showed no association (OR 0.69, 95% CI 0.27 to 1.8; moderate or high intensity versus no exposure). For extremely low frequency electromagnetic fields (EMFs), only individual data were available. An association with long occupational exposure to EMFs was found (OR 2.3, 95% CI 1.2 to 4.5). However, no effect of EMF intensity was indicated. No significant effects of benzene, gasoline or diesel, or tobacco smoking were found. OR estimates below unity were suggested for personal use of hair dye and for agricultural exposures. CONCLUSIONS: Associations between exposure to organic solvents and EMFs, and Ph+CML were indicated but were not entirely consistent.

Adult↗
PubMed2000

Surface active agents as enhancers of alveolar absorption.

PURPOSE: Small solutes which are deposited in the alveoli by aerosol inhalation will be absorbed across the alveolo-capillary barrier. Inhalation of dioctyl sodium sulfosuccinate (DOSS) enhances absorption while having little or no effect on lung function, suggesting that surface active agents may be used as enhancers of alveolar absorption of inhaled pharmaceuticals. The purpose of this study was to examine the effects of a selection of different surface active agents on alveolar absorption. METHODS: The absorption of 99mTc-diethylene triamine pentaacetate (99mTc-DTPA) from the lungs was studied in rabbits. We studied five different surface active agents: DOSS, sodium glycodioxycholate (GDCA), sodium lauryl sulphate (NaLS), lysophosphatidyl choline (LPC) and polyoxyethylene-23-laurylether (P23LE). RESULTS: DOSS and GDCA both dramatically enhanced the absorption of 99mTc-DTPA. There was a moderate effect of NaLS, no significant effect of LPC and P23LE reduced the rate of absorption. None of the compounds affected gas exchange or lung compliance. CONCLUSIONS: There is a wide spectrum of effects of inhaled surface active agents on the alveolar absorption of 99mTc-DTPA. Ionic compounds such as DOSS and GDCA have the greatest effect, and further studies of these classes of surface active agents for use as enhancers of alveolar absorption of pharmaceuticals seem warranted.

Absorption↗
PubMed2000

Survival time in a population-based consecutive series of adult acute myeloid leukemia--the prognostic impact of karyotype during the time period 1976-1993.

A consecutive population-based series of 372 adult acute myeloid leukemias, successfully cytogenetically investigated at a single center between 1976 and 1993, is reported. All medical records were reviewed in order to ascertain the prognostic impact of karyotype, divided into three groups; favorable (t(8;21), t(15;17), and inv(16) irrespective of karyotypic complexity; n = 40), poor (der(1;7), inv(3), -5, del(5q), -7, t(9;22), and complex karyotypes including whole or partial losses of chromosomes 5 and/or 7; n = 56), and intermediate (other abnormalities or normal karyotype; n = 276). The possible modification by age, gender, time period, morphologic subtype, and bone marrow transplantation (BMT) on this prognostic impact was also determined. The chemotherapy regimens used were heterogeneous over time but principally the same at any given point in time. The majority of the patients were treated with combinations including an anthracycline and cytarabine with curative intent. Gender, morphology, and BMT did not significantly modify the effect of cytogenetic patterns on survival time, whereas age and time period did. The hazard ratios for the subgroups favorable, intermediate, and poor were 1.0, 1.2 and 1.9 at age 20-49; 1.0, 2.5 and 4.5 at age 50-64; 1.0, 4.1 and 11.4 at age 65-74; 1.0, 1.4 and 2.2 for the time period 1976-1987 and 1.0, 2.0 and 6.7 for 1988-1993. The salient feature of the Kaplan-Meier curves was the improved survival during the later time period for patients with favorable and intermediate cytogenetic abnormalities. The present findings thus suggest that it is mainly these patient groups that have benefited from advances in therapy, including supportive care.

Acute Disease↗
PubMed2000

Acute myeloid leukemia and clonal chromosome aberrations in relation to past exposure to organic solvents.

OBJECTIVES: The effects of occupational and leisure-time exposures on the risk of acute myeloid leukemia (AML) were investigated with emphasis on clonal chromosome aberrations (CCA) and morphological subtypes. METHODS: Consecutively diagnosed cases of AML (N=333) and 1 population referent per case were retrospectively included in the study. Information on worktasks, companies, and leisure-time activities was obtained with telephone interviews. Exposure probability and intensity were assessed by occupational hygienists. Associations were evaluated with logistic regression. RESULTS: Exposure to organic solvents was associated with an increased risk of AML [low exposure: OR 1.5 (95% confidence interval (95% CI) 1.0-2.3, moderate-high exposure: OR 2.3 (95% CI 1.0-5.0)]. For exposure to solvents, but not to benzene, the OR was 1.2 (95% CI 0.69-2.0) for "low" and 2.7 (95% CI 1.0-7.3) for "moderate-high" exposure. The observed effects increased with intensity and duration of exposure. The estimated effects were higher for patients >60 years of age at the time of diagnosis. The effect of exposure to organic solvents was not differential with regard to morphology [except possibly erythroleukemia: OR 4.2, 95% CI 1.0-17 or the presence of CCA in general]. No increased risk for AML with complex CCA or with total or partial losses of chromosomes 5 or 7 were observed, but a higher risk was found for AML with trisomy 8 (OR 11, 95% CI 2.7-42) as the sole aberration. CONCLUSIONS: Exposure to organic solvents was associated with an increased risk of AML. This association was not due to benzene exposure alone and may be modified by age. Furthermore, specific associations with trisomy 8, and possibly also erythroleukemia, were suggested.

Acute Disease↗
PubMed1999

Isochromosome 17q in blast crisis of chronic myeloid leukemia and in other hematologic malignancies is the result of clustered breakpoints in 17p11 and is not associated with coding TP53 mutations.

An isochromosome of the long arm of chromosome 17, i(17q), is the most frequent genetic abnormality observed during the disease progression of Philadelphia chromosome-positive chronic myeloid leukemia (CML), and has been described as the sole anomaly in various other hematologic malignancies. The i(17q) hence plays a presumably important pathogenetic role both in leukemia development and progression. This notwithstanding, the molecular consequences of this abnormality have not been investigated in detail. We have analyzed 21 hematologic malignancies (8 CML in blast crisis, 8 myelodysplastic syndromes [MDS], 2 acute myeloid leukemias, 2 chronic lymphocytic leukemias, and 1 acute lymphoblastic leukemia) with i(17q) by fluorescence in situ hybridization (FISH). Using a yeast artificial chromosome (YAC) contig, derived from the short arm of chromosome 17, all cases were shown to have a breakpoint in 17p. In 12 cases, the breaks occurred within the Smith-Magenis Syndrome (SMS) common deletion region in 17p11, a gene-rich region which is genetically unstable. In 10 of these 12 cases, we were able to further map the breakpoints to specific markers localized within a single YAC clone. Six other cases showed breakpoints located proximally to the SMS common deletion region, but still within 17p11, and yet another case had a breakpoint distal to this region. Furthermore, using chromosome 17 centromere-specific probes, it could be shown that the majority of the i(17q) chromosomes (11 of 15 investigated cases) were dicentric, ie, they contained two centromeres, strongly suggesting that i(17q) is formed through an intrachromosomal recombination event, and also implicating that the i(17q), in a formal sense, should be designated idic(17)(p11). Because i(17q) formation results in loss of 17p material, potentially uncovering the effect of a tumor suppressor on the remaining 17p, the occurrence of TP53 mutations was studied in 17 cases by sequencing the entire coding region. In 16 cases, no TP53 mutations were found, whereas one MDS displayed a homozygous deletion of TP53. Thus, our data suggest that there is no association between i(17q) and coding TP53 mutations, and that another tumor suppressor gene(s), located in proximity of the SMS common deletion region, or in a more distal location, is of pathogenetic importance in i(17q)-associated leukemia.

Adolescent↗
PubMed1999

A single-center population-based consecutive series of 1500 cytogenetically investigated adult hematological malignancies: karyotypic features in relation to morphology, age and gender.

During the 18-yr period 1976-93, a population-based series of 1586 adults with suspected or confirmed hematological malignancies were successfully cytogenetically investigated at a single center. Eighty-six cases were excluded due to unretrievable medical records or if analyzed only in remission or at relapse. The remaining 1500 medical records were reviewed regarding morphology and clinical parameters in order to investigate possible associations between karyotypic pattern (normal, 1, 2 or complex anomalies; specific abnormalities) and gender, age and morphological subgroups. The impact of time-period, i.e. 1976-87 vs. 1988-93, and referring center on cytogenetic findings was also studied. A total of 372 acute myeloid leukemias (AML), 389 myelodysplastic syndromes (MDS), 64 acute lymphoblastic leukemias (ALL) and 262 chronic myeloid leukemias (CML) were identified, altogether 1087 cases. Patients with other (n=261) or no hematological malignancies (n = 152) were excluded from the present analysis. Cytogenetic abnormalities were detected in 52% AML, 51 % MDS, 68% ALL and 97% CML, frequencies that did not differ significantly between the 2 time periods or referring centers. No significant age- or gender-related differences in karyotypic patterns were discerned in AML, MDS, ALL or CML, whereas the karyotypic patterns varied among the FAB groups in both AML (p= 0.001) and MDS (p < 0.001). The specific abnormalities t(8;21), t(15;17) and inv(16) were more common (p < 0.001) in younger AML patients and 5q- was more frequent in females with MDS (p<0.001). These findings indicate, in contrast to previous series, that neoplasia-associated karyotypic aberrations are not more common among older patients or in males.

Adult↗
PubMed1999

Cytogenetic polyclonality in hematologic malignancies.

The present study was undertaken to ascertain the frequency of cytogenetic polyclonality in various hematologic malignancies and to investigate whether morphologic subgroup, age, gender, or previous genotoxic exposure influences the incidence. Among 2,243 cytogenetically investigated hematologic malignancies, 10 acute myeloid leukemias (AML), 5 myelodysplastic syndromes (MDS), 2 acute lymphoblastic leukemias (ALL), 1 acute undifferentiated leukemia (AUL), 1 atypical Philadelphia chromosome-negative (Ph-) chronic myeloid leukemia (CML), 1 chronic myeloproliferative disorder (CMD), and 1 chronic lymphoproliferative disorder (CLD) with karyotypically unrelated clones were identified, constituting 2.6% of AML, 1.6% of MDS, 0.8% of ALL, 13% of AUL, 9.1% of Ph- CML, 1.5% of CMD, and 2.8% of CLD with chromosomal abnormalities. In contrast to the cytogenetic features, the X-inactivation pattern was monoclonal in the two informative female patients that could be investigated. Among 17,733 karyotypically aberrant published cases surveyed, significant frequency differences (P < 0.001) were discerned: 1.7% of 6,526 AML, 3.4% of 2,391 MDS, 0.4% of 1,920 Ph+ CML, 2.9% of 856 CMD, 0.9% of 4,226 ALL, and 5.8% of 1,814 CLD displayed unrelated clones. The incidence of cytogenetic polyclonality did not differ significantly among the MDS, CMD, or ALL subgroups, between males and females, between children (< 16 years) and adults, or between B- and T-cell ALL, whereas the frequencies varied among the AML FAB types (P < 0.05), among the different CLD entities (P < 0.001), and between B- and T-cell CLD (P < 0.001). Furthermore, the incidence was higher in therapy-related AML and MDS than in de novo AML and MDS (P < 0.001 and P < 0.01, respectively).

Adolescent↗
PubMed1997

Diamond-Blackfan anaemia: genetic homogeneity for a gene on chromosome 19q13 restricted to 1.8 Mb.

Diamond-Blackfan anaemia (DBA; MIM#205900) is a rare disorder manifested as a pure red-cell aplasia in the neonatal period or in infancy. The clinical hallmark of DBA is a selective decrease in erythroid precursors and anaemia. Other lineages are usually normal and the peripheral white blood cell count is normal. In approximately one-third of cases, the disease is associated with a wide variety of congenital anomalies and malformations. Most cases are sporadic, but 10-20% of them follow a recessive or a dominant inheritance pattern. A female with DBA and a chromosomal translocation involving chromosome 19q was recently identified. We undertook a linkage analysis with chromosome 19 markers in multiplex DBA families of Swedish, French, Dutch, Arabic and Italian origin. Significant linkage to chromosome 19q13 was established for dominant and recessive inherited DBA with a peak lod score at D19S197 (Zmax = 7.08, theta = 0.00). Within this region, a submicroscopic de novo deletion of 3.3 Mb was identified in a patient with DBA. The deletion coincides with the translocation break-point and, together with key recombinations, restricts the DBA gene to a 1.8-Mb region. The results suggest that, despite its clinical heterogeneity, DBA is genetically homogeneous for a gene in 19q13.

Adult↗
PubMed1993

Clinical impact of breakpoint position within M-bcr in chronic myeloid leukemia.

We have analyzed the M-bcr breakpoint position in 133 Philadelphia-positive chronic myeloid leukemia patients and correlated the findings with clinical, hematologic, and cytogenetic data. We also investigated the splicing pattern of the BCR-ABL mRNA in 30 patients, using reverse transcriptase PCR. No statistically significant differences were found between breakpoint position within M-bcr and clinical parameters at diagnosis, the karyotypic evolution pattern, or the leukemic phenotype during blast crisis. Furthermore, the breakpoint position within M-bcr did not correlate with the duration of chronic phase or survival time. When the splicing pattern of the BCR-ABL mRNA was compared with the results of the genomic breakpoint mapping, it was found that approximately 60% (8/14) of the patients with a 5' break expressed b2a2 fusion mRNA, whereas all patients (10/10) with a 3' break expressed b3a2 BCR-ABL mRNA.

Adolescent↗
PubMed1992

A pilot study of piperacillin and ciprofloxacin as initial therapy for fever in severely neutropenic leukemia patients.

We studied the efficacy of piperacillin and ciprofloxacin as initial parenteral therapy in 41 adult patients with leukemia who developed 47 febrile episodes during severe neutropenia following chemotherapy. 40 patients (98%) survived their febrile episode(s), whereas 1 patient died of infection. When assessed at 72 h after initiation of treatment (early evaluation), 24/47 episodes (51%) had been successfully treated. These 24 favourable responses were seen in 15/24 (63%) microbiologically documented infections and 9/19 (47%) fever of unknown origin (FUO). At the resolution of fever (late evaluation) 46 episodes were evaluable, and 28 (61%) had responded successfully to piperacillin and ciprofloxacin. Successful treatment was most frequently observed in microbiologically defined infections, 18/23 (78%). Three of 5 (60%) Gram-positive, 11/12 (92%) Gram-negative and 1 of 2 mixed bacteremias were successfully treated. In contrast, only 10/19 (53%) FUO and none of 4 clinically defined infections had responded. Thus, this pilot study indicates that piperacillin and ciprofloxacin may be a safe and effective combination for the treatment of febrile episodes in severely neutropenic leukemia patients, which merits further investigation in randomized trials.

Adult↗
PubMed1990

Cytogenetic findings in acute megakaryoblastic leukemia (ANLL-M7).

The clinical, morphologic, and cytogenetic findings in a patient with acute megakaryoblastic leukemia (ANLL-M7) are described. At the time of diagnosis, the karyotype contained three related clones: 47,XY,t(3;6)(p13;q27), +8,t(12;22)(p13;q12), +15, -21, -22, +der(22)t(21;22)(q11;p13)/47,XY, +8,del(9)(q22),t(12;22), +15, -21, -22, +der(22)/46,XY, +8, t(12;22), -21, -22, +der(22). Complete remission was achieved with intensive combination chemotherapy. At relapse 20 months later, there was clear evidence of clonal evolution, and the karyotype was now 45,XY,t(2;18)(q33;p11),del(9)(q22),t(12;22)(p13;q12), -16, +der(16)t(8;16)(q13;p13), -21, -22, +der(22)t(21;22)(q11;p13)/46,XY,t(2;18),del(9),t(12;22), -16, +der(16), -21, -22, +der(22), +mar. A comparison with the few previously cytogenetically analyzed cases of ANLL-M7 reveals that structural rearrangements of chromosomes 21 and 22 might be of primary importance in the pathogenesis of acute megakaryoblastic leukemia.

Adult↗
PubMed1988

Chromosomes, Auer rods and prognosis in acute myeloid leukaemia.

We have analysed survival time and complete remission (CR) rate after induction treatment including cytosine arabinoside and an anthracycline antibiotic in 94 patients with acute myeloid leukaemia, comparing the results in four different groups according to the presence or absence of Auer rods and the presence (AN/AA) or absence (NN) of abnormal cytogenetic clones at diagnosis. The finding of Auer rods was a positive prognostic factor with respect to CR rate (p less than 0.02) and survival time (p less than 0.02) irrespective of the cytogenetic pattern. The AN/AA pattern was associated with lower CR rate (p less than 0.05) and 6-months survival (p = 0.05) in the 49 Auer rod-negative patients. In the 45 patients with Auer rods, no significant differences in CR rate or survival were seen between AN/AA and NN patients. We conclude that the negative prognostic impact of chromosome abnormalities in acute myeloid leukaemia might be restricted to Auer rod-negative disease.

Actuarial Analysis↗