Association of HLA-DPB with Hodgkin's disease.
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Alleles↗
Biomedical subjects
T A Lister
Publications and source records attributed to T A Lister.
Chromosome 11q23 translocations in both infant and adult acute leukemias are detected by in situ hybridization with a yeast artificial chromosome.
The yeast artificial chromosome (YAC-13HH4), which spans a 440-kb region of DNA just distal to the CD3 locus on chromosome 11 at band q23, has been used to characterize a range of chromosomal translocations in acute leukemias from both adults and infants. In situ hybridization was performed on metaphase cells from bone marrow of 17 leukemias and two cell lines with a variety of chromosome 11q23 abnormalities. It was established that in infant leukemias the translocations t(11;19), t(4;11), and t(5;11) had occurred in the region defined by YAC 13HH4. Additionally, the translocations t(4;11), t(6;11), t(9;11), t(X;11), and t(10;11) in other leukemias were found to disrupt the same region of chromosome 11q23, although an exception was found in one t(6;11) translocation for which the breakpoint was distal to the YAC. One patient had a t(9;11) translocation in a therapy-related leukemia, suggesting that this class of etoposide-related malignancy has similar breakpoints to those occurring in de novo leukemias. An example of a lymphoma-derived translocation t(4;11) was shown to involve a deletion of the region defined by YAC 13HH4. A leukemia with a deletion on chromosome 11 (q23-q25) was also studied and it was shown that the YAC sequence was unaffected. It was concluded that, with a few exceptions, the translocations at 11q23 in a wide range of acute infant and adult leukemias occur in a common region and may result from a common underlying mechanism.
Acute Disease↗
Direct sequence analysis of the t(14;18) chromosomal translocation in Hodgkin's disease.
There have been conflicting reports about the occurrence of the t(14;18) chromosomal translocation in Hodgkin's disease. A polymerase chain reaction analysis of biopsy specimens from 21 patients with Hodgkin's disease (HD) has shown the presence of the t(14;18) translocation in four cases (20%). All four patients had nodular sclerosing HD. Direct sequencing of the amplified 14q+ junctions established that the BCL-2 (major breakpoint region) sequence was fused to an Ig joining region (JH) (J6 in all four cases). Different breakpoints were observed in each case but were similar in nature to the breakpoints described in follicular lymphoma. The exact nature and cell of origin in HD remains obscure, although the presence of the t(14;18) translocation may reflect either a B-cell origin in these cases or associated lymphoid hyperplasia.
Adolescent↗
p53 expression in Reed-Sternberg cells of Hodgkin's disease.
Mutation of the p53 protein may represent the commonest genetic event in human malignancy. Abnormal p53 expression has been reported in a variety of carcinomas, sarcomas and lymphoid neoplasms; however there is little information in relation to Hodgkin's disease. The expression of the nuclear phosphoprotein was investigated in paraffin-embedded biopsies from fifty patients with Hodgkin's disease using a polyclonal antibody, CM-1 and in snap-frozen material with monoclonal antibodies, PAb 1801 and PAb 240. Specifically, immunoreactivity was localised to the Reed-Sternberg cells or mononuclear variants in both nodular sclerosing (86% cases) and mixed cellularity (57% cases) subtypes of Hodgkin's disease. However, no positive staining was found in our cases of nodular lymphocyte predominant type Hodgkin's disease. Serial biopsies following recurrence of disease demonstrated consistent results. It is suggested that overexpression of p53, probably mutant, may have a role in the tumorigenesis of Hodgkin's disease.
Hodgkin Disease↗
Role of additional radiotherapy in advanced stages of Hodgkin's disease.
Although radiotherapy is widely used as additional treatment following chemotherapy, its precise role has never been clearly proven. Relapses tend to occur in previously involved bulky sites. Non-randomized studies may suggest a positive effect of the addition of radiotherapy. This effect however, might also be caused by selection. Randomized studies have not resulted in a survival advantage for the patients treated with additional radiotherapy compared to no further treatment or additional chemotherapy. The SWOG study 7808 suggest a 20% benefit in remission duration for the nodular sclerosis histology subgroup. Definitive conclusions have to wait for more mature results of randomized studies including the ongoing EORTC study and the possibility to perform an overview of all studies.
Antineoplastic Combined Chemotherapy Protocols↗
Management of stage II Hodgkin's disease: 15 years experience at St. Bartholomew's Hospital.
One hundred seventy-seven consecutive patients with newly diagnosed stage II Hodgkin's disease (HD) (supradragmatic 157; infra diaphragmatic 20) were treated at St. Bartholomew's Hospital on the basis of pathologic stage (PS) in 84 (IIA 69; IIB 15) and clinical stage (CS) in 93 (IIA 33, IIB 60) between January 1968 and December 1984. The median follow up is 13 years. Overall, complete remission (CR) was achieved in 143 patients (75%) of whom 53 have had a recurrence. One hundred twenty-seven patients remain alive, the cumulative predicted survival at 15 yrs being 70%. Mantle radiotherapy was prescribed to 88 patients with supradiaphragmatic HD, of whom 75 entered CR and 9 achieved good partial remission (GPR) (95%). The duration of remission correlated strongly with ESR (greater than 50 mm/h) and mediastinal thoracic ratio (less than 33% vs. greater than 33%) in a multivariate analysis (p = 0.05 and 0.02, respectively). 46/88 patients remain in continuous first remission, the median duration of remission having not reached at 15 years. Combined modality therapy or chemotherapy alone was prescribed to 69 patients with supradiaphragmatic HD, CR being achieved in 51 patients and GPR in 8 at the completion of all therapy. 48/59 patients continue in first remission. The duration of remission of patients receiving combined modality therapy or CT alone was significantly longer (p = 0.002) than that of patients receiving RT alone, in spite of the fact that the former group comprised predominantly of patients with unfavourable features.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Abnormalities of chromosome 16q in myeloid malignancy: 14 new cases and a review of the literature.
Fourteen patients with abnormalities of chromosome 16q, 13 with acute myelogenous leukaemia (AML), and one with refractory anaemia with excess of blasts (RAEB), are described. Seven patients had inv(16)(p13q22), two had del(16)(q22), and five had other abnormalities of 16q. Six of the seven patients with inv(16) had AML M4Eo and, following treatment with adriamycin, cytosine arabinoside, and 6-thioguanine, all achieved complete remission (CR). Neither patient with del(16)(q22) had typical M4Eo morphology at diagnosis; CR was achieved in one and one had resistant leukaemia. Patients with other abnormalities of 16q had blasts of diverse morphology and, although morphologically abnormal eosinophils were seen in three patients, this was not as marked as in the patients with inv(16). CR was achieved in two of the four patients with other abnormalities of 16q but duration of remission was short in both cases. These results suggest that most patients with del(16)(q22) and other abnormalities of 16q22 do not have typical AML M4Eo. Such patients tend to have a worse prognosis, and are more likely to have complex karyotypes typical of secondary leukaemia.
Adult↗
The management of follicular lymphoma.
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Antineoplastic Agents↗
Interferon-alpha 2b in the treatment of follicular lymphoma: preliminary results of a trial in progress.
Since 1985 the combination of chlorambucil (10 mg daily, initially for six weeks, then alternating fortnights for 12 weeks) and interferon-alpha 2b (Schering-Plough; 2 x 10(6) U/m2 three times weekly by subcutaneous injection for 18 weeks) has been compared in a randomised trial with chlorambucil alone in previously untreated patients with stage III or IV follicular lymphoma. Responding patients have subsequently been randomised to receive maintenance interferon-alpha 2b or no further treatment. Of the 124 treated patients, 108 are evaluable for response with a median follow-up of 30 months. The major toxicity was myelosuppression which was more frequent with chlorambucil and IFN alpha 2b in combination than with chlorambucil alone (P less than 0.01). There was no treatment-related mortality. Actuarial survival at three years is 75% for all patients, regardless of therapy. There was no significant difference in response rate according to initial therapy. For the 60 patients achieving a good response to initial therapy who have entered the second part of the trial, there has been a significant prolongation of remission duration in favour of maintenance IFN-alpha 2b (median not yet reached versus two years for the 'no treatment' arm, P less than 0.015). Fewest relapses have been seen in patients who received IFN-alpha 2b throughout. Accrual to this trial continues; this preliminary analysis indicates that maintenance IFN-alpha 2b may extend remission duration in follicular lymphoma.
Adult↗
Interferon alfa-2b in addition to chlorambucil in the treatment of follicular lymphoma: preliminary results of a randomized trial in progress.
One hundred and twenty four patients with follicular lymphoma (32 with Stage III and 92 with Stage IV disease) have been randomized to receive chlorambucil alone or chlorambucil plus interferon alfa-2b. Responding patients are then randomized to receive either interferon alfa-2b maintenance therapy for up to 12 months or no further treatment. One hundred and eight patients are evaluable for response, the remainder are still receiving initial therapy. Clinical remission (complete or good partial remission) was achieved in 42/59 (71%) patients receiving chlorambucil alone and in 27/49 (55%) patients receiving the combination (P = NS). Preliminary analysis of remission duration shows a trend in favour of those patients receiving interferon throughout (P = 0.02). There is no significant difference between the groups in terms of survival, at a median follow up of 2.5 years. Interferon-associated toxicity was minor in most patients but led to discontinuation of therapy in six cases. Larger trials with longer follow-up periods are needed to confirm the beneficial role of interferon in the treatment of follicular lymphoma.
Adult↗
Chemotherapy of Hodgkin's disease.
An overall perspective of chemotherapy for Hodgkin's disease has been presented with particular emphasis on the treatment options to be considered at each stage of the disease. In 1950, M. Vera Peters ended her paper on the 'radiological' treatment of Hodgkin's disease thus: 'In the light of present knowledge the diagnosis of Hodgkin's disease should not be regarded with despair and the patient treated as incurable.... If a single ray of hope emerges from this analysis, the treatment of the individual concerned is a challenge to the combined efforts of the radiotherapist, the physician and the surgeon' (Peters, 1950). Over the ensuing 40 years, substantial progress has been made, but any further improvement must begin with an increase in the proportion of patients for whom complete remission is achieved. Prospective comparisons of hybrid regimens against standard chemotherapy are in progress and the results of these trials will hopefully answer the question as to which is the optimal regimen in the primary treatment of advanced Hodgkin's disease. The advent of growth factors may allow for an increase in dose intensity, possibly improving the results further. The role of very intensive therapy with autologous bone marrow support remains to be defined and is currently being evaluated in different trial settings. Meanwhile, the quest for alternative, less toxic compounds goes on. The challenge continues.
Antineoplastic Combined Chemotherapy Protocols↗
Computed tomography (CT) and ultrasound (US) guided core biopsy in the management of non-Hodgkin's lymphoma.
Histological examination of adequate biopsy specimens is fundamental to the management of patients with non-Hodgkin's lymphoma (NHL). A practical alternative to open biopsy, provided enough tissue can be obtained, has obvious advantages, especially if the lesion in question is deep seated, and might call for laparotomy or thoracotomy. Core biopsy with computed tomography (CT) or ultrasound (US) guidance may be such an alternative, particularly when a spring-loaded firing device is used. Thirty-four biopsies were performed in 26 patients with known or suspected NHL. A primary histological diagnosis was made in 7/7 (six NHL, one seminoma). Relapse was confirmed in 15/15 patients overall. In patients with follicular NHL, 8/15 biopsies showed progression to high grade histology. Biopsies were also performed to assess the nature of residual abnormalities after treatment and to obtain fresh tissue for immunocytochemistry. Tissue was obtained in all cases and a further procedure (two laparotomies, one second needle biopsy) was required on only three occasions. The procedure was well tolerated and there were no complications. This technique is therefore a valuable alternative to more invasive surgical procedures and may be of major benefit in the management of NHL.
Adult↗
Fludarabine phosphate for the treatment of low grade lymphoid malignancy.
Thirty-four patients with previously treated, advanced, low grade NHL were treated with Fludarabine, a deamination-resistant analogue of adenosine arabinoside, at a dose of 25 mg m-2 intravenously, daily for 5 days (median number of cycles = 3, range 1-10). Complete remission (CR) was achieved in six and partial remission (PR) in a further seven. Overall, responses were seen in 11/23 patients (48%) with follicular lymphoma and in 2/11 (18%) with low grade, diffuse NHL. Fifteen patients with previously treated CLL and one patient with prolymphocytic leukaemia (PLL) were also treated as above (median no. of cycles = 3, range 1-6). A partial response was seen in three of the 11 evaluable patients with CLL and CR was achieved in the patient with PLL. There were four deaths due to infection and 19 further episodes requiring admission to hospital. No other significant toxicity was reported in a total of 164 cycles of Fludarabine. This agent is active in advanced low grade lymphoid malignancy. Further studies are required to assess its role in newly diagnosed patients.
Antineoplastic Agents↗
Immunocytochemical demonstration of PTHrP protein in neoplastic tissue of HTLV-1 positive human adult T cell leukaemia/lymphoma: implications for the mechanism of hypercalcaemia.
The infiltrated tissues from seven West Indian patients with HTLV-1 positive adult T cell lymphoma/leukaemia (ATLL) have been analysed by immunocytochemical techniques for the presence of immunoreactive parathyroid hormone-related protein (PTHrP), a hormonal mediator of humoral hypercalcaemia of malignancy. Six of the seven were hypercalcaemic at some stage of the course of their disease. Four of the six evaluable patients showed evidence of specific cellular and extracellular expression of PTHrP protein in neoplastic tissues. This finding suggests that PTHrP may be involved in the production of hypercalcaemia in at least some cases of T cell lymphoma - proof of a causal relationship however must await the demonstration of tissue release of PTHrP resulting in raised circulating hormone levels.
Adult↗
Long term prognosis and quality of life following intensive care for life-threatening complications of haematological malignancy.
Ninety-two consecutive adult patients admitted with acute life-threatening complications of haematological malignancy were studied to determine long term outcome. The quality of life was evaluated in seven long term survivors who are currently alive more than 1 year after hospital discharge using three validated methods: the Nottingham Health Profile, the Hospital Anxiety and Depression Scale and the Perceived Quality of Life Scale. Patients were also asked whether they had returned to work, whether their daily activities were limited and whether they would be willing to undergo intensive care again under the same circumstances. The in-hospital mortality rate was 77%. Median duration of long term survival was 23 months (range 6 weeks to 8 years). Long term survival did not appear to be related to either the aetiology or the severity of the acute illness, but seemed to be determined solely by the nature and progress of the underlying malignancy. The quality of life of six of the seven long term survivors is good, while that of the other is acceptable. None of the patients reported any increased limitation of their daily activities, five had returned to full time employment and all seven stated that they would be willing to undergo intensive care again under the same circumstances.
Adult↗
New approaches to the treatment of follicular lymphoma.
The major avenues of clinical research into the treatment of follicular lymphoma, 'more, if so when?', interferon therapy, and antibody therapy, have been presented in the light of present knowledge about the clinical course of the disease. They must be seen within the context of the current philosophical approach to the illness, and the economic climate which prevails, at a time when new drugs, for example fludarabine (Leiby et al, 1987; Reman et al, 1988; Whelan et al, 1991), are showing promise, and differentiating agents are being tested in remission (Cunningham et al, 1985). There can be little doubt that the objective of future research should be to eliminate the disease altogether at the time of initial presentation, since patients entering remission and never having a recurrence have a far greater probability of longevity than those in whom recurrences occur (Lister, 1991). There can also be little doubt that when lymphoma is present and causing symptoms, treatment should be given, since survival is longer for those in whom a response is achieved, at least at presentation, and at first recurrence (Lister, 1991). Since the latter is sadly the reality for the majority, improving treatment at the time of recurrence must also be a priority. Time will tell whether any of the options presently under investigation will be appropriate at all, and if so when. It is certainly the case that some of them will be entirely inappropriate for some patients, because the risk of toxicity will outweigh the potential benefit, especially for the elderly. Further careful identification of prognostic variables may allow for individualization of therapy. It would be comforting to know that the newly found molecular marker of the disease would help us. Its absence may do--but its presence certainly does not, since t(14;18) containing cells may seemingly be present for many years of clinical normality (Price et al, 1991, in press). The challenge to find the right treatment at the right time--or perhaps to identify the 'right patient' for the therapy continues.
Antibodies, Monoclonal↗
The treatment of stage IIIA Hodgkin's disease--total nodal irradiation versus combination chemotherapy: either or neither.
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Actuarial Analysis↗
The significance of circulating cells carrying t(14;18) in long remission from follicular lymphoma.
Peripheral blood mononuclear cell fractions from 15 patients in continuous clinical remission from follicular lymphoma for longer than 10 years were examined for cells carrying the t(14;18) translocation using the polymerase chain reaction (PCR). The assay used was able to detect one positive cell in approximately 5 x 10(5) cells (a single 14q+ molecule in 2.5 micrograms DNA). Cells positive for t(14;18) were found in six of eight patients initially presenting with stage III or IV disease, compared with zero of seven of those with stage I or II disease (P less than .05). In two cases 14q+ junction regions were also successfully amplified from formalin-fixed biopsy material obtained at presentation 12 and 17 years previously. In both, sequence analysis demonstrated that the cells circulating in remission belonged to the original clone. These results indicate that cells bearing t(14;18) frequently persist in the peripheral blood in long remission of advanced follicular lymphoma and question the value of their presence as a predictor of relapse.
Adult↗