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We report four cases of unrelated adult males carrying constitutive balanced pericentric inversions of chromosome X (one case), chromosome 2 (one case), and chromosome 5 (two cases) and presenting with myeloid malignancies. We discuss the potential contribution of these abnormalities to a background of susceptibility to hematologic malignancies.

Acute promyelocytic leukemia (APL) is characterized by the t(15;17) cytogenetic abnormality leading to the expression of two fusion genes, PML/RARA and RARA/PML, and by its sensitivity to all-trans retinoic acid (ATRA) differentiating treatment. Rare APL cases lacking the t(15;17) have been described. We have previously reported two cases presenting with submicroscopic insertions of RARA or PML into chromosome 15 or 17, respectively. These insertions lead to the formation of potentially functional, nonreciprocal, PML/RARA or RARA/PML fusion genes, providing the unique opportunity to investigate in a human noncell-line model the respective role of PML/RARA or RARA/PML in retinoid signaling. Here, we report the in vitro response to ATRA of these two cases as well as of a third case presenting with submicroscopic insertion (15;17) and expressing exclusively PML/RARA, by morphological, functional, and immunological assays. The two cases expressing PML/RARA presented with an immunostaining pattern typical of APL and a positive response to ATRA, whereas the APL case expressing only a RARA/PML fusion transcript exhibited an immunostaining pattern typical of non-APL cells, and was resistant to ATRA. Our results confirm that sensitivity to ATRA requires expression of PML/RARA and strongly correlates with immunostaining, and demonstrate that expression of RARA/PML alone is sufficient for a cytological APL phenotype, but does not confer sensitivity to ATRA.

We report the case of a young adult male carrying a constitutional unbalanced t(Y;13)(q11-12;p13) leading to a partial Y disomy, and presenting successively, in a 39-month interval, with an Askin tumor and a t(8;21) acute myeloid leukemia. The origin of the two neoplasias in this patient is discussed.

This article presents a cost-effectiveness study comparing cytogenetic and molecular analyses for detection of chromosomal abnormalities which are prognostic factors in acute leukemia. The aim of the study was to determine how these two techniques could substitute or complement one another. The study sample consisted of 107 adult patients with de novo myeloid or lymphoid acute leukemias, tested by both techniques in 1994 and 1995, for identification of translocations t(9;22), t(8;21), t(15;17), t(4;11), t(1;19), the inversion of chromosome 16 and for monosomy 5 or 7 (or deletion of their long arms) and trisomy 8. The criterion for diagnostic effectiveness of these strategies was the rate of detection of true positive anomalies which are clinically relevant, according to the current state of knowledge. On the basis of these observations six alternative strategies at diagnosis were compared (each technique alone or different combinations of the two techniques). The study shows that:-for ALL, PCR alone appears the most cost-effective strategy;-for AML, cytogenetic analysis alone is the best strategy;-sequential strategies are more cost effective than simultaneous use of both techniques for minimising risk of false negatives.

Background: The use of allogeneic recombinant human granulocyte colony-stimulating factor (rhG-CSF)-mobilized blood cells was recently evaluated in patients with malignancies., Methods: Ten patients with leukemia were transplanted with allogeneic blood cells from HLA-identical sex-mismatched siblings; blood cells were mobilized with recombinant rhG-CSF. Up to 6 months after transplantation, blood and bone marrow samples were obtained from the recipient and analyzed for the presence of donor cells, using fluorescence in situ hybridization with specific probes hybridizing to sex chromosomes., Results: Analysis of blood and bone marrow smears demonstrated a complete chimera, as early as day 15 after transplantation. Furthermore, marrow and blood CD4+, CD8+, CD19+, and CD34+ cells were sorted using direct immunofluorescence and flow cytometry: fluorescence in situ hybridization analysis on sorted cells demonstrated that most progenitors and most cells in the T- and B-cell lineages were of donor origin as early as day 15 after transplantation., Conclusions: Together with recently reported results, this study demonstrates that allogeneic rhG-CSF-mobilized blood cells contain primitive hematopoietic progenitors that can repopulate all lymphoid and myeloid lineages. Establishment of chimerism seems to be quick and stable, including the T- and B-cell lineages. Although establishment of chimerism in mitogen-responsive T cells is readily assayable with conventional cytogenetics, our study provides additional insight on the reconstitution of the B lineage and T-cell subsets after allogeneic transplantation in patients with leukemia.

Pericentric inversion of chromosome 16, translocation (16;16) and del(16q), resulting in a chimerical fusion of CBFbeta and MYH11 genes, are typically seen in the M4Eo French-American-British (FAB) classification subset of acute myelogenous leukemia (AML). In this study, we analyzed 70 cases of acute non-lymphoblastic leukemia, mainly of the M4 or M5 type. We report the very unusual presence of the t(16;16) and CBFbeta/MYH11 fusion transcript in an M7 patient. Ten M4Eo and four non-M4Eo patients presented an inv(16), t(16;16) or CBFbeta/MYH11 fusion transcript. In most cases, the common 'A-type' CBFbeta/MYH11 fusion transcript was detected. In addition to the eight different breakpoints and the three alternative splicing variants already described, evidence of a new CBFbeta/MYH11 fusion transcript was found which involves a 785-bp deletion of MYH11. Moreover, two patients had an unusual transcript, to our knowledge only observed once. Only one patient had abnormal eosinophilic differentiation without chromosome 16 cytogenetic abnormalities or detectable CBFbeta/MYH11 fusion. Conversely, only one patient presented CBFbeta/MYH11 fusion without abnormal eosinophilic differentiation. Altogether, our data suggest a correlation between the CBFbeta/MYH11 fusion transcript and characteristic abnormal eosinophilic differentiation, whatever the FAB subtype or the percentage of abnormal eosinophils

The purpose of the present study was the detection of tumor cells in aphereses after mobilization of peripheral blood stem cells (PBSCs) with G-CSF from 39 breast cancer patients. Circulating tumor cells were searched using sensitive immunocytochemical technique (APAAP) with three anticytokeratin monoclonal antibodies. Counting of mononuclear cells and CD34 progenitor cells was also performed. Circulating tumor cells were detected in 35% of the patients. Cytokeratin-positive cells were detected in 45% of the patients of the metastatic group compared with 20% of the non metastatic one. Aphereses contamination was not correlated with lymph node involvement. Numbers of mononuclear cells and CD34 cells were not significantly different in positive and negative PBSCs collections. In our study, presence of tumor cells was associated with advanced clinical stage and could not be related to a higher CD34 cells mobilization by G-CSF.

Acute promyelocytic leukemia (APL; M3 in the FAB classification) is specifically associated with the t(15;17)(q23;q12) and the consequent formation of a PML/RARA fusion gene. A few cases of APL with a t(11;17)(q23;q12) and a PLZF/RARA fusion gene have recently been reported. In addition, a new variant, t(5;17)(q32;q12), with a RARA rearrangement was described in a child with atypical APL. We report an unbalanced der(5)t(5;17) in an atypical APL case showing unusual dysgranulopoiesis and some M2 features. The breakpoints were difficult to localize precisely on chromosome 5, because the translocation may have occurred on a previous del(5q). The karyotype also showed del(8q) and multiple double-minutes (dmin). Molecular studies evidenced RARA rearrangement but showed neither PML rearrangement nor PML/RARA fusion. Fluorescence in situ hybridization revealed that the dmin were of chromosome 8 origin and that they accounted for the MYC amplification observed in Southern blots. The patient did very poorly despite chemotherapy and all-trans retinoic acid (ATRA) treatment. Thus, the t(5;17) could represent a second type of variant translocation in APL that, like the disease associated with t(11;17), does not seem to respond to ATRA therapy. Whereas RARA rearrangement appears sufficient for an APL-like phenotype, it seems that the presence of a classical PML/RARA is required for typical APL with response to ATRA.

We report the case of a patient having Philadelphia-negative, bcr-abl-positive chronic myeloid leukemia. In situ hybridization showed the presence of the bcr-abl fusion on the chromosome 9 long arm in all mitoses observed. Stability of the disease was very difficult to obtain because of serious adverse effects to interferon and chemotherapy, mainly grade IV neutropenia, and a blast crisis occurred 12 months after diagnosis. Only three other patients with such presentation (Philadelphia negative, bcr-abl positive with bcr-abl fusion on the chromosome 9 long arm) have been reported, with a poor therapeutic response and outcome in two of them. Translocation of BCR to chromosome 9 may therefore have a worse prognosis than translocation of ABL to chromosome 22 in Philadelphia-negative chronic myeloid leukemia.

m-BCR chronic myeloid leukaemia (CML) is a rare entity. We report a patient presenting with Philadelphia (Ph)-positive, m-BCR-positive acute lymphoblastic leukaemia (ALL) who achieved complete remission after induction chemotherapy, but showed a majority of Ph-positive mitoses during this remission. A diagnosis of m-BCR CML was established and the patient was given interferon alpha therapy. This is the first m-BCR CML presenting as ab initio ALL. This report emphasizes the importance of karyotyping Ph-positive ALL during remission so as not to misdiagnose CML patients who can benefit from Interferon therapy.

The Philadelphia chromosome (Ph) is the cytogenetic hallmark of chronic myeloid leukaemia (CML) and is used to confirm the diagnosis of CML based on clinical and morphological criteria. We investigated 14 patients with features of CML but without detectable Ph chromosome. In seven patients, referred to as BCR+, M-bcr/abl rearrangement was detected by polymerase chain reaction (PCR). The seven remaining patients did not have M-bcr/abl rearrangement and are described as BCR-. BCR- patients were younger, had lower white blood cell counts (WBC) and lower basophilia. Four BCR- and four BCR+ patients underwent blastic transformation (BT). Response to therapy was fairly similar in both populations. According to French-American-British (FAB) Cooperative Leukaemia Group guidelines, all BCR- patients were classified as having classic form CML or 'chronic granulocytic leukaemia' (CGL) when based only on morphological data. This study further confirms the existence of true CML cases without Ph chromosome or M-bcr/abl rearrangement and shows that this entity differs only slightly from classic form Ph+ CML. The Ph-BCR- subgroup raises two problems. First, the differential diagnosis with atypical CML or CMML, based on morphological data, and secondly, the therapeutic follow-up in the absence of a specific marker. In contrast, the residual disease of Ph-BCR- patients can be monitored by PCR. More advanced molecular and biochemical techniques will be required to understand which molecular mechanisms underlie Ph-BCR- CML, resulting in phenotypes sometimes indistinguishable from Ph+ CML.

We report a Wiskott-Aldrich patient who underwent allogeneic bone marrow transplantation from his HLA-identical sister at the age of 25. Conditioning regimen consisted of cyclophosphamide (180 mg/kg) and thoraco-abdominal irradiation (6 Grays). Cytogenetic follow-up revealed rapid and complete lymphoid chimaerism, but prolonged mixed bone marrow chimaerism. Correlative interphase cytogenetics performed on bone marrow smears using dual-colour fluorescence in situ hybridization with X and Y specific probes showed that the proportion of donor cells was significantly higher within megakaryocytes than in other lineages. This patient therefore presented with dissociated lineage engraftment, which is not exceptional in congenital diseases and aplastic anaemia, but has not previously been described in Wiskott-Aldrich syndrome. Bone marrow transplantation was successful despite this delayed engraftment which ensured adequate production in the involved cell lines.

We report a pediatric case of hypereosinophilic syndrome (HES) with trisomy 8 and terminal blastic transformation to mixed acute leukaemia. Literature cases are reviewed, with emphasis on prognostic factors to differentiating "benign" from malignant HES.

The idiopathic hypereosinophilic syndrome (IHS) is extremely rare in childhood and relationships of this syndrome with myeloproliferative diseases are controversial. We reported the observation of a 7-year-old girl suffering from an IHS with myelofibrosis. A clonal cytogenetic abnormality, trisomy 8, was detected in the bone marrow cells of this child. This is the decisive proof of a myeloproliferative disorder. IHS with myelofibrosis is usually considered as unresponsive to corticotherapy. In our case, corticotherapy resulted in a rapid, complete, and lasting disappearance of myelofibrosis. Complete remission of the disease, however, was not achieved and the trisomy 8 persisted after treatment.

Ninety-two previously untreated children with ALL were admitted to the same institution between November 1984 and November 1988. According to early prognostic factors, patients were divided into 3 groups: group 1 at "low risk" for relapse (n = 18), group 2 at "intermediate risk" (n = 62) and group 3 at "high risk" (n = 12). Every patient received an 8 week-long induction chemotherapy; after CNS prophylaxis, groups 1 and 2 children received a consolidation chemotherapy and then a classical maintenance treatment. Group 3 patients were selected to receive a bone-marrow transplantation during their first remission because of the presence, at diagnosis, of at least one of the following criteria: hyperleukocytosis greater than 100,000 (7 cases), translocation t(1;19) and t(4;11) (2 cases), adolescents (2 cases), no remission at day 30 (2 cases). Ninety-one of 92 children achieved a complete remission and none died during induction therapy. Probability of leukemia-free survival at 4 years is 73 +/- 7% for the whole patient population and 95%, 71% and 60% for patients of groups 1, 2, and 3 respectively. Persistence or disappearance of leukaemic cells in bone marrow after the initial 15 days of chemotherapy appears to influence the probability of a leukemia-free survival.