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Biomedical subjects

J A Yin

Publications and source records attributed to J A Yin.

At least 37 records · Page 2Linked to original sources
PubMed1996

Evaluation of cytogenetic conversion to Ph- haemopoiesis in long-term bone marrow culture for patients with chronic myeloid leukaemia on conventional hydroxyurea therapy, on pulse high-dose hydroxyurea and on interferon-alpha.

Long-term bone marrow culture (LTBMC) has been used successfully in autologous transplantation in chronic myeloid leukaemia (CML). However, variation between patients in the recovery of Ph- cells in culture limits the application of this procedure to a minority. Treatment that effectively reduces in vivo tumour burden prior to initiation of LTBMC may improve the selection of Ph- cells in culture. To test this hypothesis we evaluated the frequency and degree of cytogenetic conversion to Ph- haemopoiesis in LTBMC from four independent groups of CML patients: Untreated (n = 19); conventional dosage of hydroxyurea (HU) (n = 10); pulse high-dose HU (P-HU) (n = 22) and interferon (IFN)-alpha (n = 12). In this study IFN-alpha therapy resulted in a significantly higher incidence of patients with detectable Ph- clonogenic cells in the marrow (P = 0.01) and with > or = 50% Ph- haemopoiesis in LTBMC as compared to newly diagnosed patients (P = 0.05). Also, sequential culture studies undertaken in 14 CML patients at diagnosis and following the start of pulse highdose HU therapy showed that in eight patients the average proportion of Ph- metaphases detected in LTBMC substantially increased from 1.7% (range 0-7) at diagnosis to levels of 71% (range 14-100) after treatment. Therefore we conclude that the use of IFN or pulse high-dose HU in early stage disease appears to create an opportunity to harvest the marrow for long-term culture (LTC) purging with reduced leukaaemic burden.

Adult↗
PubMed1996

Clonality switch in acute myeloid leukemia.

We have previously described a case of clonality switch in a female patient with acute myeloid leukemia (AML) by X-chromosome inactivation analysis. She presented with refractory anemia with excess blasts in transformation but soon progressed to overt AML. Following induction chemotherapy, she went into complete remission but later relapsed into a second myelodysplastic phase. Analysis of her X-linked DNA polymorphism patterns at presentation and relapse showed that hematopoiesis was clonal, but the genotypes of the two clones was different. She remains clinically well and has a virtually normal blood count more than 5 years from presentation. We now report an update of this unique case and discuss the implications of this finding within the context of a multicellular origin of leukemia.

Adult↗
PubMed1995

Validation of a model to predict survival in elderly patients with acute myeloid leukaemia.

Intensive chemotherapy is the treatment of choice for selected elderly patients with acute myeloid leukaemia (AML). We recently developed a model to predict survival, thereby providing objective information upon which to select appropriate therapy for such patients. Such models, however, must be validated on a cohort of patients not used during the development of the model. We have tested the model using a series of 61 elderly patients consecutively treated with intensive chemotherapy. Using several statistical techniques, we have shown that the model is of value in predicting prognosis, though two patients did markedly better than the model prediction. This model may be useful for predicting survival in elderly patients with AML and warrants more extensive validation.

Acute Disease↗
PubMed1995

Persistence of RAR alpha-PML fusion mRNA detected by reverse transcriptase polymerase chain reaction in patients in long-term remission of acute promyelocytic leukaemia.

Acute promyelocytic leukaemia (APL) is characterized by t(15;17), which results in the formation of two chimaeric genes, PML-RAR alpha and RAR alpha-PML. PML-RAR alpha transcripts have been detected in all cases of APL whilst those of RAR alpha-PML have been detected in only about 67% of cases. We have used reverse transcriptase polymerase chain reaction (RT-PCR) to detect both fusion transcripts serially in 18 patients in remission of APL after chemotherapy and bone marrow transplantation. All patients were negative for PML-RAR alpha, whereas in six patients (remission 3-9 years) RAR alpha-PML was consistently detected. Only one patient at remission showed the 5' breakpoint RAR alpha-PML, with the rest showing the 3' breakpoint 144 bp RAR alpha-PML. The level of sensitivity for detecting RAR alpha-PML was some 10-fold higher than that for PML-RAR alpha. Serial negative tests for PML-RAR alpha have been correlated with durable remissions, suggesting possible eradication of residual leukaemia in APL. Our results, however, show persistence of t(15;17) cells expressing RAR alpha-PML fusion mRNA in patients in long-term remission of APL. They indicate that patients considered clinically 'cured' of APL still have molecular evidence of minimal residual disease and also provide further insight into the biology of acute myeloid leukaemia.

Base Sequence↗
PubMed1995

Immunostaining of whole agar cultures by APAAP.

We have adapted the alkaline phosphatase-anti alkaline phosphatase (APAAP) technique to demonstrate cell antigen distributions in intact agar culture. The method facilitates batch processing and is no less convenient to perform than standard APAAP procedures. Myeloid and lymphoid antigens generally demonstrated strong staining intensity. However, staining at day 0 consistently produced no antigen expression for two monoclonals (CD11c and CD34) in contrast to positivity in parallel cytospins. CD11c showed rapidly increasing antigen expression over subsequent days of culture whereas the expression of CD34 could not be shown in conventional agar culture at any time from day 0 to day 14. Positivity was only restored in CD34-positive leukaemic cells using a modified culture technique in which cells were cultured as pre-formed small aggregates. Assessment of these aggregates extended to cell cycle analysis using anti-bromodeoxyuridine. CD71 positivity in normal culture samples correlated with colony configuration (whether clones were 'spread' or 'tight' in appearance). CD38 staining of normal bone marrow culture at day 7 showed asymmetrical staining of cells in a small number of micro-groups. The clonal detection of aberrant antigens (CD7, CD2) for assessment of minimal residual disease in AML was a disappointment due to the relative frequency of positive clones in normal culture.

Agar↗
PubMed1995

Clonality studies in patients undergoing allogeneic and autologous bone marrow transplantation for haematological malignancies.

Twenty three allogeneic bone marrow transplant (BMT) patients with female donors and 23 female autologous transplant patients were assessed for clonality status after transplant to determine the nature of haemopoietic reconstitution. The X chromosome probes PGK, HPRT and M27 beta were used to assess clonality by analysis of X chromosome inactivation. Results were obtained for 15 allogeneic patients, 14 of whom gave polyclonal results after transplantation. One patient gave a skewed pattern of X chromosome inactivation after transplant due to extreme Lyonisation of the donor cells. Results were obtained from 19 autologous transplant patients, 17 of whom gave polyclonal results after transplant. Two patients gave patterns of skewed X chromosome inactivation in post-transplant samples, reflected in their constitutive DNA, due to extreme Lyonisation. The remaining patients could not be assessed because of hypermethylation of HpaII sites or indistinguishable digested and undigested alleles using M27 beta probe analysis. Haemopoietic reconstitution after allogeneic and autologous BMT, in our patients, was found to be polyclonal. Skewed patterns of X chromosome inactivation seen after transplant were due to extreme Lyonisation of the infused haemopoietic cells.

Bone Marrow Transplantation↗
PubMed1994

Detection of t(8;21) by reverse transcriptase polymerase chain reaction in patients in remission of acute myeloid leukaemia type M2 after chemotherapy or bone marrow transplantation.

Seven patients with acute myeloid leukaemia (AML) type M2 and t(8;21), treated with intensive chemotherapy followed in two cases by allogeneic or autologous bone marrow transplant (BMT), were tested for the presence of transcripts of the characteristic chimaeric gene AML1/ETO by reverse transcriptase polymerase chain reaction (RT-PCR) at serial intervals during remission. Six patients, including both BMT patients, demonstrated persistence of t(8;21), one being consistently negative in peripheral blood but bone marrow positive. Bone marrow may, therefore, be more reliable than peripheral blood for detecting residual t(8;21) cells. Our results show persistence of t(8;21) cells in AML-M2 patients following chemotherapy or BMT, some of whom were in long-term remission.

Adult↗
PubMed1994

Therapy-related acute promyelocytic leukaemia.

We report three patients with acute promyelocytic leukaemia (APL) occurring after treatment for other malignant disorders. One patient had had razoxane (a drug affecting DNA topoisomerase II) for cancer of the colon, and the other two had had treatment for cancer of the breast. Two out of the three patients went into complete remission. We review the published literature on therapy-related acute promyelocytic leukaemia (t-APL) and suggest that it is a genuine clinical entity which may be caused by drugs affecting DNA topoisomerase II, and has a prognosis similar to de novo APL.

Adult↗
PubMed1994

P-glycoprotein expression on acute myeloid leukaemia blast cells at diagnosis predicts response to chemotherapy and survival.

P-glycoprotein (Pgp) expression, which is associated with the multi-drug resistance (MDR) phenotype, has been reported to be a useful predictor of treatment outcome in acute leukaemia. We have examined the expression of Pgp on acute myeloid leukaemia (AML) cells in 54 newly diagnosed patients, using a novel streptavidin-biotin complex (ABC) technique. 55% of patients at diagnosis were positive for Pgp with JSB-1, a monoclonal antibody that binds to an internal epitope of Pgp. All patients received intensive induction chemotherapy. Post-remission treatment consisted of further chemotherapy +/- bone marrow transplantation. Complete remission (CR) rates were significantly lower in the Pgp positive group than in the Pgp negative group (60% v 92%; P = 0.02). The overall survival for Pgp-positive patients was significantly shorter (329 v 534d, P = 0.004), disease-free survival was also reduced but the difference was not statistically significant (median 277 v 522d, P = 0.16). In this study CD34 expression was not predictive of response to chemotherapy nor was it associated with Pgp expression. Our results confirm the prognostic value of Pgp expression in AML at diagnosis and we suggest that Pgp could be a useful therapeutic target for reversing multi-drug resistance. Furthermore, our simple and sensitive method of detecting Pgp should enable widespread testing to be performed.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Influence of azathioprine on the ferrokinetics of patients with renal failure before and after treatment with erythropoietin.

In 16 patients (9 on azathioprine, 7 not) the ineffective iron turnover (IIT) was much higher in the azathioprine group (62.7 +/- 6.7 vs. 23.5 +/- 3.5 mumol/l blood/day, p < 0.0001, 2-tailed t test), though the red cell iron turnover (RCIT) was similar (42.8 +/- 2.9 vs. 41 +/- 4.8). Erythropoietin improved the anaemia in all patients and raised the RCIT (4 still on azathioprine to 72.2 +/- 9.8, p < 0.003; 7 non-azathioprine patients to 62.7 +/- 5.3, p < 0.01); the IIT remained higher in the azathioprine-treated (85.5 +/- 19.3 vs. 37.1 +/- 5.4; p < 0.013). In 2 patients who discontinued azathioprine, the IIT declined markedly to normal. In summary, azathioprine exacerbates the anaemia of renal failure by augmenting ineffective erythropoiesis, while erythropoietin benefits those on azathioprine as much as other renal patients by stimulating both effective and ineffective erythropoiesis.

Anemia↗
PubMed1994

Abnormal synthesis of 1,25-dihydroxyvitamin D in patients with malignant lymphoma.

High serum concentrations of 1,25-dihydroxyvitamin D [1,25-(OH)2D] can occur with hypercalcemia in malignant lymphoma. We have investigated the potential for abnormal vitamin D metabolism by giving a single oral dose of 25-hydroxyvitamin D (25OHD) in 10 lymphoma patients (8 Hodgkin's and 2 T-cell) and 7 controls. Serum 25OHD increased similarly in both groups (peak concentrations, 114.1 +/- 9.5 vs. 123.9 +/- 9.6 nmol/L). In controls, serum calcium and PTH did not change after treatment [calcium, 2.31 +/- 0.02 and 2.33 +/- 0.02 mmol/L (mean +/- SEM); PTH, 21.6 +/- 4.0 and 25.4 +/- 4.3 ng/L] 1,25-(OH)2D increased within the normal range from [median (range)] 81 (48-125) to 117 (91-156) pmol/L. In lymphoma patients, serum calcium increased from 2.29 +/- 0.04 to 2.40 +/- 0.06 mmol/L (P = 0.03), PTH decreased from 12.9 +/- 2.6 to 8.0 +/- 1.9 ng/L (P = 0.06), and one patient became hypercalcemic (2.92 mmol/L). Serum 1,25-(OH)2D became supranormal in 6 lymphoma patients; the group median rose from 74.5 (46-180) to 151 (120-487) pmol/L; this peak response differed from that in the controls (P = 0.019). Lymph node and spleen cells from a patient with T-cell lymphoma synthesized [3H]1,25-(OH)2D3 from [3H] 25OHD3 in vitro. The data suggest that abnormal production of 1,25-(OH)2D in lymphoma may be more common than previously recognized given an adequate supply of precursor 25OHD and provide further evidence for the extrarenal synthesis of 1,25-(OH)2D in this condition.

Calcifediol↗
PubMed1994

Prognostic factors in elderly patients with acute myeloid leukaemia.

Acute myeloid leukaemia (AML) is predominantly a disease of the elderly; the median age of incidence is 64 years, and 60% of all cases are over 60. With improved chemotherapy regimens and maximal supportive care, remission rates of up to 60% may be achieved in selected elderly patients. Whilst intensive chemotherapy is the treatment of choice for fit patients, it may be inappropriate for debilitated patients with poor prognosis disease in whom supportive care or palliative chemotherapy may be more suitable. AML in the elderly exhibits biological differences from AML in younger patients, and elderly patients may be unable to withstand the rigors of the intensive treatment regimens given to younger patients. We review methods to evaluate prognostic factors, the development and application of prognostic models, and available data regarding prognostic factors in elderly patients with AML. We discuss a rationale for the use of prognostic factors in selecting therapy for patients and for tailoring of therapy according to disease and host related variables.

Adolescent↗
PubMed1993

Relapsed myelodysplastic clone differs from acute onset clone as shown by X-linked DNA polymorphism patterns in a patient with acute myeloid leukemia.

We have used a recombinant strategy based on X-chromosome-linked restriction fragment length polymorphisms to analyze clonality in a female patient with acute myeloid leukemia (AML). She presented with features compatible with a diagnosis of refractory anemia with excess of blasts in transformation, but soon progressed into overt AML. Intensive chemotherapy successfully induced a complete remission, but she later relapsed into a second myelodysplastic phase. Although analysis at presentation and relapse showed that hematopoiesis was clonal at both phases of the patient's disease, the genotype of the two clones was different. We believe the unexpected finding of a switch in clonality shows new insights into the biology and origin of AML.

Adult↗
PubMed1993

Acute ischaemia of the lower limb: an unusual presenting feature of acute lymphoblastic leukaemia.

Malignant disease is often complicated by coagulation disorders presenting as abnormal clotting or bleeding, acute leukaemia being more often associated with the latter. Acute lymphoblastic leukaemia presenting with peripheral arterial thromboembolism, previously unreported in the literature, is presented. Aetiology, clinical features, and management of coagulation disturbances associated with malignancy are also reviewed.

Adult↗
PubMed1993

Prognostic factors in elderly patients with acute myeloid leukaemia: development of a model to predict survival.

With an increasing number of elderly patients presenting with acute myeloid leukaemia and with recent reports of worthwhile remission rates and survival times following treatment with intensive chemotherapy, there is a pressing need to identify criteria to assist in the selection of appropriate therapy for elderly patients. We have performed multivariate Cox proportional hazard regression analysis of data prospectively collected during the treatment of 104 patients aged 60 and over treated in a multi-centre study with a standardized regimen of mitozantrone and cytosine arabinoside for induction and consolidation. Four readily available parameters, namely urea, performance status, peripheral blood blast count and presence of hepatomegaly, were identified from which a prognostic model to predict survival has been developed. The model was found to be accurate in predicting survival in the cohort of patients from which it was developed, but needs to be validated in a further test population studied prospectively. Its simplicity suggests that it may be particularly useful in the selection of elderly patients with AML most likely to benefit from intensive chemotherapy.

Acute Disease↗
PubMed1993

Effects of azathioprine on response of renal anaemia to subcutaneous recombinant human erythropoietin.

AIMS: To determine the effect of concomitant azathioprine treatment on the response of patients with renal failure to treatment with subcutaneous recombinant human erythropoietin (r-HuEPO). METHODS: Two groups of patients with renal failure not receiving haemodialysis were studied. One comprised seven patients receiving erythropoietin alone, the second consisted of nine patients who were also treated with azathioprine. The haematological changes were monitored, and the functional erythropoietic response was studied by two different ferrokinetic models. One analysed the initial, the other the extended plasma iron clearance. Studies were performed before r-HuEPO treatment on all 16 patients, and repeated on 11 of these when the target haemoglobin (10-11 g/dl) was achieved and stabilised. Total erythropoiesis was determined using both techniques. Analysis of the extended plasma iron clearance also permitted calculation of both effective and ineffective erythroid activity. RESULTS: The haematological response to r-HuEPO was the same for both patient groups. Measurement of total erythropoiesis by both ferrokinetic methods showed good correlation. For those receiving long term azathioprine, the percentage ineffective erythropoiesis was high compared with that of the other patients, and remained so for as long as they continued with azathioprine. For those uncomplicated by azathioprine treatment, r-HuEPO increased levels of both effective and ineffective erythropoiesis by the same degree. A substantial reduction in ineffective erythropoiesis was shown only by those patients who either discontinued or reduced their azathioprine once they started r-HuEPO treatment. CONCLUSIONS: Azathioprine increases ineffective erythropoiesis. In this study, the r-HuEPO dose was sufficient to overcome this effect and promoted effective erythropoiesis so that the anaemia lessened. Measurement of total erythropoiesis provided limited information on the functional changes involved, differentiation of effective from ineffective erythropoiesis being necessary to define the changes after azathioprine reduction or withdrawal.

Anemia↗