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Biomedical subjects

John Swansbury

Publications and source records attributed to John Swansbury.

At least 19 recordsLinked to original sources
PubMed2005

Long remissions in hairy cell leukemia with purine analogs: a report of 219 patients with a median follow-up of 12.5 years.

BACKGROUND: Both pentostatin and cladribine have efficacy in hairy cell leukemia (HCL), but it is not known which agent achieves better results. METHODS: We reviewed a series of 219 patients with HCL, with median follow-up from diagnosis of 12.5 years (range 1.0 -34.6 yrs), treated with either pentostatin (n = 185) or cladribine (n = 34), to compare these agents and assess the potential for cure. RESULTS: Overall response to pentostatin was 96% with a complete response (CR) in 81% and a median disease-free survival (DFS) of 15 years. Response to first-line cladribine was 100% with a CR in 82% and DFS of 11+ years. The relapse rates at 5 years and 10 years were 24% and 42%, respectively, with pentostatin, and 33% and 48% with cladribine. Survival at 10 years was respectively 96% and 100%. CR rates decreased with each sequential relapse through 69% to 45% (P < or = 0.001). Patients achieving CR after first-line treatment had a significantly longer DFS (P = 0.00007) than those achieving a partial response; a similar result was seen after second-line therapy (P = 0.00001). DFS also declined with sequential treatment (P = 0.00005). CONCLUSION: We have shown equivalent efficacies for both agents in the treatment of HCL, with DFS showing no plateau. True cure in HCL remains elusive, but the addition of monoclonal antibodies may be beneficial. Our results suggest that achieving CR should remain the main goal of treatment.

Antibiotics, Antineoplastic↗
PubMed2005

Zeta-chain associated protein 70 and CD38 combined predict the time to first treatment in patients with chronic lymphocytic leukemia.

BACKGROUND: Zeta-chain associated protein (ZAP)-70 has been proposed as a surrogate marker for immunoglobulin heavy-chain variable region (IgVH) mutation in chronic lymphocytic leukemia (CLL), but it is still not clear whether it is an independent prognostic factor. METHODS: The authors evaluated ZAP-70 expression by flow cytometry in 201 untreated patients and correlated ZAP-70 levels with CD38 expression, genetic abnormalities detected by fluorescence in situ hybridization (FISH), and the time from diagnosis to first treatment. RESULTS: Fifty-seven patients (28%) were positive for ZAP-70 (> or = 20%). Positive ZAP-70 status was associated with advanced disease stage, atypical morphology, CD38-positive status, trisomy 12, del(6q), or no detectable abnormalities; negative ZAP-70 status was correlated with del(13q) as a sole abnormality. The treatment-free interval (TFI) was 17.7 months for ZAP-70-positive patients and 44.6 months for ZAP-70-negative patients (P < 0.001). Multivariate analysis in 117 patients identified advanced stage, CD38 > or = 7%, and the absence of del(13q) as a sole abnormality as independent factors for short TFI. Excluding FISH, ZAP-70 status acquired independent prognostic value along with CD38 status. The authors proposed a risk model that combines ZAP-70 and CD38 to identify patients who are likely to progress. When both markers were positive, the TFI was 12 months; when both were negative, the median TFI was 54 months; a median TFI of 26 months was observed in patients who had discordant results (P < 0.00001). CONCLUSIONS: The current findings suggested that both ZAP-70 and CD38 should be tested prospectively in all patients with early-stage CLL.

ADP-ribosyl Cyclase 1↗
PubMed2005

Comparative genomic hybridization and BUB1B mutation analyses in childhood cancers associated with mosaic variegated aneuploidy syndrome.

We previously demonstrated that constitutional BUB1B mutations cause mosaic variegated aneuploidy, a condition characterized by constitutional aneuploidies and childhood cancer predisposition. To further investigate the role of BUB1B in cancer predisposition we performed comparative genomic hybridization analysis in an embryonal rhabdomyosarcoma from an MVA case with biallelic BUB1B mutations, revealing aneuploidies typical of sporadic E-RMS, with gain of chromosomes 3, 8, 13 and loss of chromosomes 9, 14, X. To investigate whether somatic BUB1B mutations occur in sporadic childhood cancers we screened 30 Wilms tumours, 10 acute lymphoblastic leukemias, nine rhabdomyosarcomas and 11 rhabdomyosarcoma cell lines for BUB1B mutations. We identified seven exonic and six intronic variants. Six of the exonic variants were synonymous and one resulted in a non-synonymous conservative missense alteration that was also present in a control. These data suggest that the genetic progression in rhabdomyosarcoma from MVA and non-MVA cases may be similar, but that somatic BUB1B mutations are unlikely to be common in sporadic childhood cancers known to be associated with MVA.

Aneuploidy↗
PubMed2005

Delayed response to fludarabine in lymphoplasmacytic lymphoma/Waldenström's macroglobulinemia.

We retrospectively reviewed time to response and incidence of delayed responses in 13 patients with lymphoplasmacytic lymphoma/Waldenstrom's macroglobulinemia (LPL/WM) treated with fludarabine with or without cyclophosphamide. During follow-up post-treatment, seven delayed responses (54%) were observed, improving the initial overall response rate of 61% to a final response rate of 77%.

Adult↗
PubMed2004

Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B.

Mosaic variegated aneuploidy is a rare recessive condition characterized by growth retardation, microcephaly, childhood cancer and constitutional mosaicism for chromosomal gains and losses. In five families with mosaic variegated aneuploidy, including two with embryonal rhabdomyosarcoma, we identified truncating and missense mutations of BUB1B, which encodes BUBR1, a key protein in the mitotic spindle checkpoint. These data are the first to relate germline mutations in a spindle checkpoint gene with a human disorder and strongly support a causal link between aneuploidy and cancer development.

Abnormalities, Multiple↗
PubMed2004

Isolated bone marrow involvement in diffuse large B cell lymphoma: a report of three cases with review of morphological, immunophenotypic and cytogenetic findings.

Diffuse large B cell lymphoma (DLBL) comprises a heterogenous entity characterized by the presence of large cells, exhibiting a mature B cell phenotype. The high proliferation rate and aggressive disease remain a therapeutic challenge, but the apparent biological diversity permits a risk-stratification model for prognostic grouping through the International Prognostic Index (IPI). Empirical to this approach is the consideration of cytogenetic data, offering an insight into the pathogenetic events which may underlie neoplastic clonal evolution and disease progression. We describe three cases of DLBL presenting with isolated marrow disease, a rare primary finding in this lymphoma. All three cases showed involvement of blood and bone marrow without evidence of splenic or lymph node involvement on imaging studies. Histological and immunophenotypic findings were similar in all three cases, outlining the phenotypic maturity of this disease. Cytogenetic analysis revealed complex karyotypes in the two cases examined. M-FISH (multicolour fluorescent in situ hybridization) performed on bone marrow from case 1 showed several cryptic translocations not evident on G-banding, including a novel translocation between 2p and 9p, and an unbalanced translocation between 14q and 11q. Cytogenetic analysis in case 2 showed abnormalities involving 7q, 9p at the site of the INK4a gene, and the bcl-2 locus, findings confirmed by M-FISH. These cases serve to highlight the biological and cytogenetic heterogenity of DLBL and emphasize the need for complementary investigations in the characterization of this entity.

Adult↗
PubMed2003

Delineation of the minimal region of loss at 13q14 in multiple myeloma.

Previous studies have focused on the incidence and prognostic implications of 13q14 deletions in multiple myeloma (MM), but none has sought to delineate the minimal common deleted region (CDR). In an effort to do so, dual-color interphase fluorescence in situ hybridization (FISH) was applied on 82 myeloma cases, initially by use of three probes for 13q14 (RB1, D13S319, and D13S25). Deletions were detected in 29/82 (35.4%) cases, and all except one were monoallelic. Subsequently, contiguous YACs, PACs, and a BAC spanning the 13q14-q21 region were employed for deletion mapping in addition to a 13q telomere probe. Large deletions extending to the 13q34 region were found in 55% of the deleted cases, whereas an additional 13.8% showed loss of both 13q34 and 13q14 regions with retention of 13q21. A CDR of approximately 350 kb was identified at 13q14 with the proximal border approximately 120 kb centromeric from D13S319, encompassing an area rich in expressed sequence tagged sites and containing DLEU1, DLEU2, and RFP2 genes. Direct sequencing of the RFP2 gene revealed no mutations in six patients and four MM cell lines harboring deletions of the CDR. However, a role for RFP2 in the pathogenesis of MM cannot yet be excluded, given that alternative mechanisms such as haploinsufficiency remain possible.

Adult↗
PubMed2003

The myeloid disorders: background.

Myeloid disorders do not usually present quite so many technical challenges to the cytogeneticist as does ALL: the chromosomes are often of a better quality, and white blood cell counts are not usually so high, except in CGL. Unlike in the chronic lymphoid disorders, there is no need for mitogens to include cell division. However, apart from the Ph in CGL, the overall frequency of detected clones is not so high. This has the consequence that a large proportion of patients is denied the diagnostic and prognostic benefit of knowing the cytogenetic abnormalities that are associated with their disease.

Chromosome Aberrations↗
PubMed2003

Acute lymphoblastic leukemia: background.

Acute lymphoblastic leukemia is a fascinating disease for the cytogeneticist, as so many cases have a clone detectable by cytogenetics or FISH, and because identifying the abnormalities provides such useful information to the clinician. However, it is also a frustrating disease, as it has technical challenges such as a marked tendency for the sample to clot during harvesting, frequently poor chromosome morphology, and, especially in the high count cases, failure to provide any divisions at all for analysis. For these reasons, this book includes two chapters on the practical aspects of undertaking cytogenetic studies in ALL to illustrate contrasting approaches. The first is from a laboratory that is a world leader in its success rates, which has an enviably low sample/cytogeneticist ratio, and which is usually able to expect a good-sized sample commensurate with the importance given to a diagnostic cytogenetic study. The second is from a laboratory that also has a good success rate, despite having to cope with a higher workload and often much smaller samples. This is not to imply that each technique is limited to such circumstances; both are worthy of study and emulation.

Bone Marrow↗
PubMed2003

Lymphoid disorders other than common acute lymphoblastic leukemia: background.

The cytogenetic abnormalities that are found in chronic lymphoid malignancies (and in acute leukemias deriving from relatively mature cells) fall mainly into two groups according to whether the malignant cells are of B-lineage or T-lineage. In most of the B-lineage cases. there is some abnormality of the IgH gene which is located at 14q32 or, less frequently, the other immunoglobulin genes located at 2p12 and 22q11. In the T-lineage cases, there is often some abnormality involving the T-cell receptor loci, most frequently those at 14q11. Other abnormalities occur, but few have a close association with a particular disease type, and so do not often contribute to determining a precise diagnosis. This lack of specificity is due partly to deficiencies in our understanding of the biological relationships between different lymphoid disorders, and also to the various classifications that have been used. As a consequence, there has to be some doubt about the diagnosis assigned to many of the cases in published cytogenetic studies. It is also difficult to combine data from series that have used different classification systems. The present unsatisfactory situation greatly limits the clinical usefulness of cytogenetic studies and there is a real need to unravel the complexities of this large family of malignancies.

Chromosome Aberrations↗
PubMed2003

Cytogenetic and genetic studies in solid tumors: background.

Cytogenetic and genetic studies of solid tumors are an area of continuing rapid growth and discovery. They provide an excellent resource for students interested in research, but more importantly have the potential to benefit patients. As has already happened in the leukemias, identifying certain genetic abnormalities can establish a definite diagnosis and/or can indicate likely response to treatment. Other chromosome abnormalities are ubiquitous, such as rearrangements of chromosome 1, and do not appear to correlate with other clinical features; however, even abnormalities of this sort serve to distinguish between malignancy and reactive conditions. Trisomy 7 is also common in many kinds of tumor and has been found as the sole abnormality in cells from tissues surrounding a tumor; the significance of this is not clear: Either trisomy 7 is associated with some reactive response in normal cells, or else it was a primary clonal abnormality and indicated the presence of infiltrating early malignant cells.

Cytogenetics↗
PubMed2003

Some difficult choices in cytogenetics.

In making a selection of features of these technologies, it is inevitable that some will be omitted that other cytogeneticists feel should have been included. The author could probably justifiably be accused of bias. However, based on experience in a laboratory that has used almost every type of assay mentioned in this chapter, the following opinions are offered about their current value in providing a routine malignancy cytogenetics service: 1. The foundation is still a conventional cytogenetic study, preferably with the use of an automated karyotyping system. 2. Added to this, there should be the capability of performing FISH studies using chromosome paints and gene-specific probes. Cytogenetics and FISH form a powerful partnership when backed by experienced cytogeneticists. MFISH or SKY are also useful if the laboratory can afford the considerable extra expense. CGH and fibre FISH are generally better suited to research projects, and at present have few applications in a routine diagnostics service. 3. At present, molecular methods such as RT-PCR mostly tend to produce results that have a greater need of confirmation by other techniques before they can be used for clinical management.

Cytogenetics↗