Carotid stump syndrome: outcome from surgical management.

OBJECTIVES: in patients with occluded internal carotid arteries the carotid stump is a potential source of microemboli resulting in the persistence of retinal or cerebral ischaemic symptoms. We report 25 patients who had persistent cerebral and retinal ischaemic symptoms with an occluded ipsilateral ICA and a carotid stump who underwent surgical exclusion of the stump. METHODS: between January 1988 and January 1998, 332 patients underwent carotid endarterectomy. Twenty-five patients (20 males: five females; mean age 58.9 (range 44-78 years)) had carotid stump exclusion. Indications for surgery were transient ischaemic attack (22), amaurosis fugax (eight) and cerebrovascular accident (13). Three patients had undergone contralateral carotid endarterectomy and 12 had significant contralateral stenosis. Twenty patients were being treated with aspirin and four with warfarin at the time of presentation. RESULTS: the diagnosis of carotid stump was made in 22 patients by angiography. In the remaining three patients duplex alone was diagnostic in two patients. In the third case duplex was combined with magnetic resonance angiography (MRA) to confirm the diagnosis. Stump exclusion was carried out by oversewing the ICA origin. All but one patient remained symptom free at follow-up. CONCLUSION: carotid stump syndrome should be considered as a likely clinical entity in patients with an occluded ICA and persisting cerebral and retinal microembolic symptoms. Surgical exclusion of the carotid stump is a safe and effective method of treatment.

A greater incidence of complex translocations in myeloid leukemias than in lymphomas and lymphoid leukemias associated with IGH rearrangement.

We have shown that the incidence of complex translocations is approximately the same in chronic myeloid leukemia, characterized by the t(9;22)(q34;q11), and in acute myeloid leukemias, characterized by the t(15;17)(q22;q11) or t(8;21)(q22;q22). This incidence is almost threefold greater than the incidence of complex translocations in lymphomas and lymphoid leukemias characterized by the t(8;14)(q24;q32) or t(14;18)(q32;q21). The genomic recombination, which gives rise to the translocations in lymphoid cells, results mostly from errors of IGH gene rearrangement. Genomic recombination underlying myeloid leukemias has a different cause, and a clue to this may lie in the greater incidence of complex chromosome rearrangements.

Growth characteristics in vitro of myeloid leukaemic cells with t(6;9).

We report an analysis of in vitro growth characteristics of leukaemic cells from five patients with t(6;9)(p23;q34). Consistent with other reports of this abnormality, our patients were comparatively young (median age at diagnosis, 29 years), and responded poorly to conventional treatment (median survival from diagnosis, 10 months). During active disease the CFU-GM growth patterns were characterized by an abundance of granulocytic aggregates (mostly 20-100 cells in size) whose leukaemic origin was confirmed by cytogenetic analysis. During remission induction, colonies derived from regenerating normal progenitor cell colonies could be distinguished from those derived from persisting leukaemic cells on the basis of differences in size, morphology, in situ staining characteristics, and karyotype. Remission growth patterns were those of a normal bone marrow. Our findings add to a growing recognition that the t(6;9) identifies a subset of leukaemic patients with distinctive clinical, haematologic, molecular, and in vitro growth characteristics for whom conventional treatment offers little hope of cure or long survival.

Deletion 20q in association with Philadelphia chromosome positive acute lymphoblastic leukemia. A report of two cases.

Cytogenetic deletions involving the long arm of chromosome 20 are thought to be characteristic of myeloid disorders. We report clinical and cytogenetic observations of two adult patients with Philadelphia chromosome positive acute lymphoblastic leukemia: one with a smaller 20q deletion that was the sole cytogenetic abnormality in a persisting remission clone, the other with a larger 20q deletion that was a late addition to the leukemic clone at disease relapse following allogeneic bone marrow transplantation.

Mosaicism with a normal cell line and an autosomal structural rearrangement.

Over three decades, 12 cases of mosaicism for an autosomal rearrangement were recognised in the major cytogenetics laboratories in New Zealand, eight of which were studied between 1990 and 1992. One case inferentially involved the gonad, eight the soma, and three both gonad and soma. This mosaicism could have arisen as a postzygotic event either in a conceptus that was initially normal, with the generation of an abnormal cell line, or in a conceptus having a supernumerary chromosome which was lost at a subsequent mitosis, thereby restoring a normal cell line. Three of the 12 cases involved a presumed direct duplication, an otherwise very uncommon rearrangement. This may indicate a propensity for direct duplications to arise at mitosis rather than at meiosis; unequal sister chromatid exchange is a plausible mechanism. Mosaicism has clinical relevance for genetic counselling, as an intragonadal cell line carrying a rearrangement could generate multiple unbalanced gametes. Mosaicism for an autosomal rearrangement my be very much more common that is, or ever could be, recognised.

DNA sequence analysis of the major breakpoint cluster region of the BCR gene rearranged in Philadelphia-positive human leukemias.

We sought sequence characteristics that might explain the apparent high recombination frequency of the 5-kb BglII segment containing M-bcr exons 1, 2 and 3, and the intron to exon 4. An Alu sequence (subfamily Sx), in 5'-->3' orientation, lay in the middle of a 3-kb region that contains the great majority of Philadelphia chromosome breakpoint sites. The breakpoint of only one out of five chronic myeloid leukemia patients, for whom the BCR breakpoint site had been sequenced, was located within this Alu. Other features of interest for recombination were a 51-bp AT-rich region close to the 3' end, six hypervariable minisatellite consensus octamers, GC[A/T]GG[A/T]GG, six lymphoid recombinase heptamer signal sequences, one nonamer and a 16-bp inverted repeat. Dot matrix comparisons of the 5-kb M-bcr sequence with a 3-kb m-bcr2 segment showed significant homology only in corresponding Alu sequences.

Trisomy 18 mosaicism with complete peripheral lymphocyte trisomy and normal intelligence.

We report a patient with trisomy 18 in all peripheral lymphocytes, mosaicism in cultured fibroblasts, mild nonspecific dysmorphic features, and normal intelligence. Trisomy 18 mosaicism with complete peripheral lymphocytic trisomy has not been previously described. The karyotype of lymphocytes is not diagnostic in the absence of congruent morphologic features.

Complex chromosomal translocations in the Philadelphia chromosome leukemias. Serial translocations or a concerted genomic rearrangement?

Joining of the BCR and ABL genes is an essential feature of the group of human leukemias characterized by the Philadelphia chromosome and there is recent evidence that the human BCR-ABL fusion gene induces leukemia in experimental animals. Joining of these two genes is the result of cytogenetic translocation, usually the t(9;22)(q34;q11), but sometimes of more complex translocations involving one or more chromosomes in addition to chromosomes 9 and 22. The leukemic cells of some patients carry the BCR-ABL fusion gene but have an apparently normal karyotype. Recent studies show that these cells conceal complex chromosome rearrangements. Because the BCR-ABL fusion gene appears to be the result of cytogenetic rearrangement in all cases of these leukemias, the causes and mechanism of chromosome rearrangement will be relevant to the development of leukemia in man. We examine mechanisms of chromosome rearrangement and propose that both simple and complex chromosome translocations result from a single, though sometimes complex, interchange event.

Molecular definition of interstitial deletions of chromosome 13 in leukemic cells.

Three patients with leukemia and one with a myeloproliferative disorder carried an interstitial deletion of chromosome 13, del(13)(q12q14), in leukemic cells. Proximal and distal breakpoints of the deleted segment were characterized by using DNA restriction fragment length polymorphisms of chromosome 13 supplemented by quantitative densitometry of hybridization signals to determine the copy number of individual loci. Both proximal and distal breakpoints varied between patients, and it is unlikely that a significant hybrid gene was formed by rejoining at the breakpoint junctions. The retinoblastoma gene was encompassed by the deleted segment in all four patients.

Entire ABL gene is joined with 5'-BCR in some patients with Philadelphia-positive leukemia.

In four patients, the chromosome 9 breakpoint of the t(9; 22)(q34;q11) had occurred at different sites within an 8.25-kilobase (kb) region situated 5' of ABL exon 1B. Chromosome in situ hybridization and field inversion gel electrophoresis (FIGE) studies showed that ABL exons 1A and 1B were present on the Ph chromosome. Yet this large fusion gene produced an mRNA conventional for chronic myelogenous leukemia (CML). Splicing from BCR exon 3 to ABL exon 2 crossed more than 200 kb and deleted exons 1A and 1B. This breakpoint site may occur in about 10% of all CML patients. Three of our patients have pronounced thrombocytosis, and two had been diagnosed as having Ph-positive essential thrombocythemia. The platelet count of the other patient was not available.

Localization of the TRK proto-oncogene to human chromosome bands 1q23-1q24.

A FER-related sequence isolated from a human genomic library was found to be homologous to TRK. In situ hybridization of a 0.92 kb probe, isolated from this sequence, localized the TRK gene to the long arm of chromosome 1 within bands 1q23-1q24. This is a significantly more proximal location of TRK than the 1q32-1q41 site published recently (Miozzo et al., 1990).

Ph-negative chronic myeloid leukemia: molecular analysis of ABL insertion into M-BCR on chromosome 22.

Leukemic cells from a patient with Ph-negative chronic myeloid leukemia (CML) had a normal karyotype. M-BCR was rearranged and chromosome in situ hybridization showed an ABL insertion between 5' and 3' M-BCR on an apparently normal chromosome 22. The association of 5' BCR and 3' ABL at the 5' junction of the chromosome 9 insert was typical of that found for the BCR-ABL fusion gene in other patients with the standard t(9;22) and CML. With an M-bcr-3' probe, we cloned and characterized a 3' junction fragment. Field inversion gel electrophoresis and chromosome in situ hybridization studies using a probe isolated from genomic DNA 5' of the junction showed that 3' M-BCR was joined to a region of chromosome 9q34 rich in repetitive sequences and lying some distance 3' of ABL. The chromosome 9 insert was at least 329 kilobases long and included 3' ABL and a larger portion of chromosome 9q34. Our results allowed us to exclude transposon- or retroviral-mediated insertion of ABL into chromosome 22. Instead, we favored a two-translocation model in which a second translocation reconstituted a standard t(9;22)(q34;q11) but left the chromosome 9 insert, including 3' ABL, in chromosome 22.

Syndrome of a craniofacial dysostosis, limb malformation, and omphalocele.

We describe an infant with a unique combination of a severe craniofacial dysostosis and a very distinctive facies, severe limb defects, a thoracic deformity, and an omphalocele as the major anomalies. We propose that this represents a "new" syndrome of multiple congenital abnormalities.

Localization of the SRC oncogene to chromosome band 20q11.2 and loss of this gene with deletion (20q) in two leukemic patients.

In situ hybridization of the pHul-c-src probe to metaphase cells from three normal donors and two leukemic patients showed significant labeling in the proximal region of the long arm of chromosome 20q, with modal peaks of grains consistently at band 20q11.2. A secondary peak of grains was detected in the region 20q13.2-qter, the localization of SRC suggested by previous in situ studies. The exact localization of SRC is important for understanding the del(20q) chromosomal abnormality in myeloid neoplasias. Chromosome in situ hybridization and genomic studies showed loss of one allele of SRC in two patients with the deletion (20q). These results differ from previously published findings and suggest heterogeneity of the breakpoint at 20q11.2 in interstitial deletions of 20q, which characterize myeloid disorders.

The variable hematologic expression of the BCR-ABL genomic mutation and its possible determinants.

The Philadelphia (Ph) chromosome usually results from the t(9;22), which causes the physical association of the BCR1 and ABL genes and their function as a single new gene. This precise genomic mutation probably has a significant role in the development of leukemia in humans, but that leukemia may take several forms: chronic myeloid leukemia (CML), acute myeloid leukemia, acute lymphocytic leukemia, and essential thrombocythemia; CML also transforms to a lymphoid or myeloid acute phase. Two models are considered with regard to determinants of this variable hematologic expression of BCR-ABL. The first is variation in the breakpoint site of BCR1. Two breakpoint sites, M-BCR and m-BCR, are known, and their occurrence shows a nonrandom association with the different forms of leukemia. The precise position of the breakpoint within M-BCR may also be important. The second model concerns the role of other genes in determining the leukemic form shown by BCR-ABL. Results are reviewed of a patient who entered blast crisis CML and whose leukemic clones involved ten genetic loci with known leukemic associations. Many of these were probably genetic variants that allowed leukemic proliferations following the initiation of blast crisis. The multiplicity of these genes may obscure the prime determinant of blast crisis, which is unknown at the present time.

HRAS1 and INS genes are relocated but not structurally altered as a result of the t(7;11)(p15;p15) in a clone from a patient with acute myeloid leukaemia (M4).

A patient whose leukaemic cells carried the rare t(7;11)(p15;p15) was diagnosed as having acute myelomonocytic leukaemia (AML-M4), and supports the association of this specific translocation with forms of acute myeloid leukaemia showing differentiation. Blast phase chronic myeloid leukaemia was excluded by lack of involvement of the ABL and BCR genes. Chromosome in situ hybridization studies showed that both the HRAS1 and INS genes were present on the terminal part of chromosome 11p which was translocated to chromosome 7p. Neither HRAS1 nor INS were structurally rearranged. Field inversion gel electrophoresis showed that a 400 kb fragment encompassing HRAS1 was structurally entire in leukaemic DNA. Because the INS gene, which was also translocated, is probably located proximal to HRAS1 on chromosome 11p, it is unlikely that HRAS1 was near the chromosome 11 breakpoint or involved in this leukaemia.

Localization of human c-mos to chromosome band 8q11 in leukemic cells with the t(8;21) (q22;q22).

Chromosome in situ hybridization studies locate c-mos to chromosome band 8q11 in leukemic cells carrying the t(8;21) (q22;q22). This amends the previous assignment of c-mos to chromosome band 8q22 and conforms with its recent assignment to 8q11 in normal cells and in a cell line with a structurally abnormal chromosome 8. C-mos lies proximally to, and distant from, the breakpoint at 8q22 in the t(8;21) and is unlikely to have a role in the onset of acute myeloid leukemia characterized by this translocation.