J. A. Whittaker

Parenteral glutamine protects hepatic function during bone marrow transplantation

Hepatic veno-occlusive disease (VOD) of the liver is a common complication following high-dose cytotoxic therapy for bone marrow transplantation (BMT). The major pathological changes are seen in centrilobular (zone 3) hepatocytes and adjacent endothelium. Glutathione (GSH) becomes depleted following chemotherapy and experimental evidence suggests reduced levels predispose to centrilobular hepatocyte and endothelial cell injury. Animal studies have shown that glutamine infusions can maintain GSH levels and protect against free radical injury. We have prospectively studied the effect of glutamine supplementation during BMT. Thirty-four patients undergoing BMT were randomised to receive either glycl-L-glutamine (n = 18) or an isonitrogenous mixture of non-essential amino acids (n = 16). Glutamine was shown to significantly preserve protein C (days +4 and +7, P < 0.05) and albumin levels (days 0 and +4, P < 0.02). markers of thrombin and plasmin generation (thrombin-antithrombin, prothrombin fragment f1+2 and plasmin-antiplasmin levels) were not significantly changed between the two groups. these findings suggest that glutamine preserves hepatic function but does not alter thrombin or plasmin generation during bmt. previous studies have shown reductions in protein c, albumin, factor x and factor vii levels post bmt. falling protein c levels have been shown to be predictive of severe vod. these data suggest a role for glutamine in the protection of hepatic function following bmt.

Clonal lymphocytes are detectable in only some cases of MDS

Clonal analysis of lymphocytes from patients with myelodysplastic syndrome (MDS) has been carried out using X‐chromosome inactivation patterns detected by the probe M27β, and by polymerase chain reaction amplification of the immunoglobulin heavy chain gene hypervariable region, CDR3. Of 32 female patients heterozygous for M27β only seven (22%) demonstrate monoclonality of peripheral blood lymphocytes. 12 (37%) give unequivocal polyclonal results and the remaining cases give patterns of X‐inactivation which cannot be interpreted either way. A study of 68 MDS patients showed five (7%) with a population of B‐cells with a monoclonal rearrangement of CDR3 compared with none out of 60 normal individuals, none out of 15 with B‐non Hodgkin lymphoma (B‐NHL) in remission and 19 out of 25 (75%) of cases of B‐chronic lymphocytic leukaemia (B‐CLL). Monoclonal lymphocytes were found by both techniques in only two females with MDS. We conclude that the presence of polyclonal lymphocytes is a common finding in patients with MDS.

Patterns of care and survival for adolescents and young adults with acute leukaemia – a population-based study

SummaryWe report a population-based study of patterns of care and survival for people with acute leukaemia diagnosed at age 15–29 years during 1984–94 in regions of England and Wales covered by specialist leukaemia registries. There were 879 patients: 417 with acute lymphoblastic leukaemia (ALL) and 462 with acute myeloid leukaemia (AML). For ALL, actuarial survival rates were 43% at 5 years after diagnosis and 37% at 10 years. Survival improved significantly between 1984–88 and 1989–94 for those aged 15–19 at diagnosis. Patients entered in national clinical trials and those not entered had similar survival rates. Survival rates were similar at teaching and non-teaching hospitals and at hospitals treating different numbers of study patients per year. For AML, survival rates were 42% at 5 years after diagnosis and 39% at 10 years. Survival improved significantly between 1984–88 and 1989–94. Patients entered in the Medical Research Council AML10 trial had a higher survival rate than those who were in the earlier AML9 trial. Survival did not vary with category of hospital. We conclude that survival has improved for adolescents and young adults with acute leukaemia but that there is at present no evidence that centralized treatment results in a survival benefit for patients in this age group.

A prospective study of psychosocial morbidity in adult bone marrow transplant recipients

Forty recipients of bone marrow transplantation were recruited prospectively and assessed pretransplant, at 1 month postdischarge, and at 6 months postdischarge between 1989 and 1990. Assessments included a psychiatric interview, a variety of standardized questionnaires (Hospital Anxiety and Depression Scale, Mental Attitude to Cancer Scale, Psychosocial Adjustment to Illness Scale), and a standardized diagnostic interview. The influence of factors such as depression and anxiety upon length of stay, survival, psychosocial adjustment, and negative prognostic attitudes were examined. In contrast to other studies, little influence was found for psychiatric illness on physical outcome variables, but they did affect psychosocial outcome. The implications of these findings are discussed.

A Retrospective Study of Psychosocial Morbidity in Bone Marrow Transplant Recipients

Of the 44 bone marrow transplant recipients asked to participate in this study, 33 completed psychometric instruments. Twenty-five patients had both unstructured clinical interviews and interviews using a structured diagnostic instrument (the Composite International Diagnostic Interview). There were no differences between allogeneic and autogenic transplant recipients. Overall, patients demonstrated adjustment comparable with other medical patients. A high prevalence of depression (40%) was shown to be associated with impaired function. The implications of these findings are discussed.

Evaluation of erythropoiesis after bone marrow transplantation: quantitative reticulocyte counting

Erythroid regeneration is an important and separate element in the engraftment process in allogeneic and autologous bone marrow transplantation (alloBMT, autoBMT). Qualitative visual reticulocyte counting has proved inadequate in the evaluation of erythropoiesis after BMT but automated flow cytometry now allows the reliable quantitation of reticulocytes even to very low levels. Reticulocyte counts and highly fluorescent reticulocyte (HFR) counts (very early reticulocytes) were estimated daily in recipients of 22 autoBMT and 14 alloBMT using a Sysmex R‐1000 automated reticulocyte counter. Marrow ablation caused an immediate and rapid fall in both the reticulocyte count and the HFR. Measurable numbers of reticulocytes persisted throughout the hypoplastic period, but HFR fell to zero in the majority of both the autoBMT and alloBMT. HFR rose significantly after a median time of 14 d post‐autoBMT, and 12 d post‐alloBMT. Attainment of 15 × 109/l reticulocytes and 0·5 × 109/l HFR at day 21 post‐transplant was associated with ultimate engraftment in 100% cases. Inadequate engraftment was seen in the majority of patients whose responses fell below these levels. Graft‐versus‐host disease was associated with a transient slight reduction in reticulocyte count. Neither episodes of infection nor blood transfusions had any significant impact on trends of reticulocytes or HFR.

The cystic fibrosis ΔF508 gene mutation and cancer

Following the observation that relatives of cystic fibrosis (CF) patients have an increased mortality due to leukaemia, a study was initiated to determine whether leukaemia patients had an increased prevalence of the ΔF508 CF mutation. No increase in carriers were found among leukaemias; however the carrier frequency of the ΔF508 mutation appeared to be reduced in patients with malignant melanoma analysed as a control group compared to the normal population. This paper extends our previous study and investigates several other common human tumours, including those of the colon, breast, and lymphoma tissue. Fewer than expected carriers remained among the melanoma group from South Wales. There were fewer than expected carriers among patients with colon cancer compared to the normal population. The prevalence of the ΔF508 mutation was normal in lymphomas and leukaemias. Hum Mutat 10:45–48, 1997.

FMS mutations in patients following cytotoxic therapy for lymphoma

Point mutations at codons 301 and 969 of the FMS proto-oncogene have been reported in both myelodysplasia (MDS) and acute myeloid leukaemia (AML). We report here the incidence of such mutations in patients at risk of developing secondary MDS and AML. Peripheral blood DNA from 70 patients in remission from lymphoma was screened for mutations by oligonucleotide (ONH) using mutant specific probes. Codon 969 mutations were detected in 11 of the 70 (15.7%) cases. No codon 301 mutations were detected. Five of these mutations were confirmed using an independent technique (single nucleotide primer extension analysis, SNPE) and a further mutation was detected in a single patient using single-stranded conformational polymorphism analysis (SSCP). No codon 969 mutations were detected in 62 lymphoma biopsy specimens from these patients or from three patients with detectable FMS mutations where pre-therapy marrow was investigated by ONH. No mutations at either codons 301 or 969 were detected by ONH in 61 normal controls. Somatic mutations at codon 969 of the FMS gene occur commonly following cytotoxic therapy for lymphoma and their detection indicates the presence of a clonally expanded population of abnormal cells.

HISTOCOMPATIBILITY ANTIGEN DR4 IS ASSOCIATED WITH CHRONIC GRAFT‐VERSUS‐HOST DISEASE IN THE SOUTH WALES POPULATION

Chronic graft-versus-host disease (cGVHD) is characterized by involvement principally of the skin, eyes and GI tract (Shulman et ul, 1980). It occurs typically more than 100 d post bone marrow transplantation (BMT) and can arise de novo or follow acute GVHD which confers a worse prognosis (Sullivan et al. 1987). The major recognized risk factors for cGVHD are increasing age of recipient and seventy of acute GVHD (Storb et al. 1983). The exact mechanism of cGVHD is unknown, but it is believed to involve allo-reactive nonspecific suppressor T lymphocytes. cGVHD has clinical similarities to systemic lupus erythematosis. scleroderma and Sjogren’s syndrome. Many diseases are now known to have an association with specific histocompatibility antigens (HLA). We have investigated the possibility ofan HLA linkage with cGVHD. At the time of study, 28 patients who had received HLA fully matched allogeneic BMT were available for evaluation. HLA-A, B and DR typing was performed on all patients and potential donors prior to BMT. Fully matched subjects (i.e. HLA-A and HLA-B compatible with a negative mixed lymphocyte reaction (MLR)) were harvested to provide donor marrow. Of the 28 BMT, only two were from matched unrelated donors. Post BMT immunosuppression was achieved by the use of cyclosporin alone and acute GVHD was treated with high-dose steroids. Assessment of cGVHD has been made by repeated clinical examination and, where indicated, biopsy of affected tissue. Patient details are provided in Table I.

Spontaneous remission in chronic lymphocytic leukaemia.

Chronic lymphocytic leukaemia (CLL) is often an indolent disease which may only produce symptoms and signs at an advanced stage. Clinical staging schemes (Rai et al. 1975: Binet et al, 1981) have been useful in determining prognosis and therapeutic options. Once diagnosed, CLL must be monitored over long periods of time. Such serial observations may show that the disease is stable or that abnormal lymphocytes are accumulating which has prognostic significance. However, once established, the disease is usually persistent, but variably progressive. We report three cases of spontaneous complete remission in CLL.