Comorbidity in multiple sclerosis: its temporal relationships with disease onset and dose effect on mortality.

BACKGROUND AND PURPOSE: We aimed to determine the burden of comorbidities at the time of diagnosis of multiple sclerosis (MS), the risk of developing new comorbidities after diagnosis and the effect of comorbidities on mortality in patients with MS. METHODS: This study used data from 2526 patients with incident MS and 9980 age-, sex- and physician-matched controls without MS identified from the UK Clinical Practice Research Datalink. RESULTS: Before the MS diagnosis, the adjusted odds ratio for the association between MS and a Charlson comorbidity index score of 1-2, 3-4 or ≥5 was 131 [95% confidence interval (CI), 1.17-1.47], 1.65 (95% CI, 1.20-2.26) or 3.26 (95% CI, 1.58-6.70), respectively. MS was associated with increased risks of cardiovascular and neurological/mental diseases. After diagnosis, the adjusted hazard ratio for the association between MS and an increased risk of developing comorbidities was 1.13 (95% CI, 1.00-1.29). The risk of developing any comorbidity in terms of neoplasms, musculoskeletal/connective tissue diseases or neurological/mental diseases was higher in MS. Patients with MS had a higher mortality risk compared with controls, with a hazard ratio of 2.29 (95% CI, 1.81-2.73) after adjusting for comorbidities. There was a dose effect of pre-existing comorbidities on mortality. CONCLUSIONS: Patients with MS have an increased risk of developing multiple comorbidities both before and after diagnosis and pre-existing comorbidities have an impact on survival.

Epilepsy and associated mortality in patients with multiple sclerosis.

BACKGROUND AND PURPOSE: We aimed to determine the prevalence of epilepsy in patients with multiple sclerosis (MS) at diagnosis, the risk of developing epilepsy after the diagnosis of MS and the relative risk of mortality associated with epilepsy. METHODS: We used the UK Clinical Practice Research Data-link to identify 2526 patients with incident MS and 9980 age-, sex- and index year-matched non-MS controls from 1997 to 2006. Logistic regression was used to estimate odds ratios [95% confidence interval (CI)] for epilepsy and Cox regression was used to estimate hazard ratios (HRs) (95% CI) for epilepsy and mortality. RESULTS: Patients with incident MS were on average 45 years old and 70.9% were female. At diagnosis, the prevalence of epilepsy in patients with MS was 1.30% compared with 0.57% in non-MS controls. At diagnosis, MS was associated with an adjusted odds ratio (95% CI) of 2.11 (1.36-3.27) for pre-existing epilepsy. Among epilepsy-free patients, the cumulative probabilities of developing epilepsy, first recorded within 10 years of the index date, were 2.77% for patients with MS and 0.90% for controls. MS was associated with an adjusted HR (95% CI) of 6.01 (2.94-12.29) for epilepsy. Among patients with MS, epilepsy was associated with an HR (95% CI) of 2.23 (1.02-4.84) for all-cause mortality. CONCLUSIONS: This population-based study found an increased prevalence of epilepsy in patients with MS at diagnosis when compared with non-MS controls and the risk of developing epilepsy was also higher following the MS diagnosis. Patients with MS with epilepsy had a higher risk of mortality compared with those without.

Enrollment of patients to clinical trials in haematological cancer in New South Wales: current status, perceived barriers and opportunities for improvement.

BACKGROUND: Enrolment of cancer patients in clinical trials is associated with significant positive outcomes. There are, however, limited Australian data on enrolment of patients with haematological malignancies to clinical trials. AIM: The aim of this study is to document the number of patients with haematological malignancies enrolled on clinical trials in NSW, to establish the barriers to trial recruitment and to examine possible means by which clinical trials participation may be improved. METHODS: Quantitative data on clinical trial accrual were obtained from all sites participating in clinical trials in haematological malignancies in NSW from 2004 to 2007 and were compared with the cancer incidence data for that period. Qualitative data on barriers and strategies for improvement were gathered using semi-structured interviews with clinical trials professionals from throughout NSW. RESULTS: Between 2004 and 2007 there were significant increases in the number of active centres, clinical trials and trial participation, and by 2007, 10.5% of all eligible patients with haematological malignancies in NSW were enrolled in relevant clinical trials. Resource constraints were the greatest perceived barrier to participation, but the success of clinical trials is also challenged by difficulties associated with communication, ethics review, trial coordination, trial design and support for emerging centres. CONCLUSION: While participation in clinical trials in haematological cancer in NSW improved between 2004 and 2007, participation in clinical trials remains suboptimal. The development of specific strategies to address barriers to participation may facilitate increased enrolment and ultimately improve clinical outcomes in patients with haematological malignancies.

Consensus guidelines for 'rainy day' autologous stem cell harvests in New South Wales.

Autologous stem cell transplantation (ASCT) has a well-established role in the treatment of haematological malignancies. Stem cells are commonly collected following salvage chemotherapy although there may be advantages in collecting earlier in the disease course. A 'rainy day' harvest (RDH) refers to the collection of autologous haemopoietic stem cells for long-term storage. Although there are few data to support RDH, there is increasing evidence that such harvests are being carried out, creating storage pressures in stem cell laboratories across New South Wales. The Bone Marrow Transplant Network New South Wales conducted a three-staged exercise to develop consensus-based RDH guidelines. Using available evidence, guidelines were developed supporting RDH for specific patients with acute and chronic myeloid leukaemias, follicular and other lymphomas, and multiple myeloma. Physician agreement with these disease-specific guidelines ranged between 58 and 100%. These consensus guidelines will improve equity of access to appropriate RDH and assist the planning of future storage requirements in New South Wales.

Feasibility and efficacy of maintenance chemotherapy following autologous bone marrow transplantation for first remission acute lymphoblastic leukaemia.

Thirty-eight patients with poor risk ALL in first remission received maintenance chemotherapy following ABMT. Patients were conditioned for ABMT with high-dose melphalan and single fraction total body irradiation. Maintenance chemotherapy was commenced in a total of 26 patients and was tolerated to a median daily dose of 6-mercaptopurine of 40.5 mg/m2 and a median weekly dose of MTX 8.3 mg/m2. Twenty patients remain alive in first remission with a projected disease-free survival of 50% and a median follow-up in survivors of 200 weeks (range 48-387 weeks). Eleven patients have relapsed at a median of 4.5 months from ABMT. These patients were compared with remission patients with ALL receiving conventional chemotherapy on the United Kingdom Medical Research Council trials UKALL X and XA. After stratifying for major risk factors and allowing for the delay from remission to transplant, we have shown a significant reduction in the risk of relapse after ABMT (p = 0.04). Disease-free survival was not significantly increased due to transplant-related toxicity. This study suggests that maintenance chemotherapy to prevent relapse after ABMT for ALL is well tolerated and warrants assessment in a formal controlled trial.

Tumour lysis following hydrocortisone prior to a blood product transfusion in T-cell acute lymphoblastic leukaemia.

The acute tumour lysis syndrome is a well recognised complication of chemotherapy for lymphoid malignancies. There are few reports, however, of this complication after corticosteroid therapy alone. We report a case of T-cell acute lymphoblastic leukaemia who developed the biochemical picture of tumour lysis after two doses of hydrocortisone given prior to platelet transfusion. Prophylactic corticosteroids prior to blood product infusion should be reserved for patients who have experienced febrile or allergic reactions in the past and it is suggested that they should only be administered to patients with active lymphoid malignancies with due caution.

Results of a double blind placebo controlled study of ondansetron as an antiemetic during total body irradiation in patients undergoing bone marrow transplantation.

Total body irradiation (TBI) is a highly emetogenic component of the majority of conditioning regimens in use for bone marrow transplantation. Conventional antiemetic therapy fails to control nausea and vomiting induced by single fraction TBI in as many as 50% of patients. In a double blind study of 20 patients undergoing marrow transplantation, a single 8 mg ondansetron dose was compared with placebo given immediately prior to TBI. Our routine premedication of phenobarbitone and corticosteroid was also administered to all patients. All patients had received high dose melphalan the previous evening. Only 1 of the 10 patients in the ondansetron group experienced an emetic event compared with 5 of the 10 in the comparison group (p = 0.029). No significant adverse events were observed. Ondansetron appears to have extremely useful antiemetic activity during single fraction low dose rate TBI.

No increase in relapse in patients with myeloid leukaemias receiving rhGM-CSF after allogeneic bone marrow transplantation.

Twenty patients with leukaemia received recombinant human GM-CSF (rhGM-CSF) after allogeneic bone marrow transplantation (BMT) in a double blind controlled trial, with a significant promotion of granulopoiesis when compared with 20 control patients. The follow-up in survivors is now sufficiently long to assess the potential for promotion of relapse in the patients with myeloid leukaemias. Six patients with myeloid leukaemias are alive 22-38 months after transplantation. Eight other patients with myeloid leukaemias died within 12 weeks of transplantation without active active disease. None of these 14 patients with myeloid leukaemias have relapsed. This study supports the view that rhGM-CSF does not increase the probability of relapse after allogeneic BMT in patients with myeloid leukaemia.

Human recombinant GM-CSF in allogeneic bone marrow transplantation for leukaemia: double-blind placebo controlled trial.

A double-blind randomised trial compared 20 patients with leukaemia receiving human recombinant granulocyte macrophage colony stimulating factor (GM CSF), with 20 patients receiving placebo for 14 days after allogeneic matched sibling bone marrow transplantation. The median neutrophil count at 14 days was significantly higher in the GM CSF group (1.90 vs. 0.46 x 10(9)/l). The duration of hospital stay, the number of antibiotic days, and the number of fever days was the same for both patient groups. The lymphocyte count was significantly higher in the GM-CSF group than in the placebo group between days 10 and 15 after transplantation. The GM-CSF group had lower haemoglobin concentrations and platelets counts, and higher plasma urea creatinine and bilirubin, than the placebo group. There was no evidence that GM CSF was associated with a greater incidence of leukaemic relapse.

Ex vivo release of GABA from tetanus toxin-induced chronic epileptic foci decreased during the active seizure phase.

Injecting a few mouse LD(50) of tetanus toxin into rat hippocampus has been shown to induce a remarkably persistent sequence of functional changes which provide a chronic model of limbic epilepsy. Here we have measured the release of amino acid transmitters evoked by K(+)-stimulation from hippocampal slices prepared from rats which had been injected 10-14 days previously with 6 mouse LD(50) (c. 3 ng) of tetanus toxin. The Ca(2+)-dependent component of the release of [(14)C]?-aminobutyric acid (GABA) was depressed to two thirds its control level. Rats which had survived 6-8 weeks, by which time the seizures had ceased, showed a recovery of the Ca(2+)-dependent component of the K(+)-evoked release of GABA to control levels, but these rats also exhibited a paradoxical depression of the Ca(2+)-independent component of release. [(3)H]d-Aspartate has previously been used as a putative marker for excitatory amino acid release. However, it failed to fulfil this role in the present study because its release was not stimulated by K(+). In contrast [(3)H]d-aspartate was released in response to veratrine. Together with previous work this suggests that while [(3)H]d-aspartate was taken up into neurones, it did not enter the releasable vesicular pool. HPLC measurements of the release of endogenous excitatory amino acids showed that glutamate (and not aspartate) was stimulated by K(+) in a Ca(2+)-dependent manner, and that the amount of release did not differ in the tetanus toxin-injected rats. The depression of GABA release provides the most likely mechanism for the seizures. The recovery of its Ca(2+)-dependent release provides the most likely basis for seizure remission after 6-8 weeks, in this chronic epileptic syndrome.

Acute Myeloid Leukaemia Following Matched Allogeneic Bone Marrow Transplantation for T-Cell Lymphoblastic Lymphoma.

It is now commonly acknowledged that cells from some acute leukaemias may bear both myeloid and lymphoid markers at diagnosis, or that relapse following initial treatment may occur, with blast cells phenotypically different from those seen at initial diagnosis. Patients showing evidence of bi-linear disease seem to carry a worse prognosis for cure. Here, a case of T-cell lymphoblastic lymphoma is reported, who relapsed with acute myeloblastic leukaemia, following allogeneic bone marrow transplantation. Early diagnosis of disease with lymphoid and myeloid features is therefore warranted, so that intensive treatment programmes may be offered, in anticipation of permanent cure.

Human recombinant GM-CSF in allogeneic bone-marrow transplantation for leukaemia: double-blind, placebo-controlled trial.

In a randomised, double-blind trial 20 patients with leukaemia received human recombinant granulocyte macrophage colony-stimulating factor (GM-CSF) and 20 received placebo, for 14 days after allogeneic, matched sibling, bone-marrow transplantation. The neutrophil count recovered to 0.5 x 10(9)/l 3 days earlier in the GM-CSF group than in the placebo group (not significant), and the median neutrophil count at 14 days was significantly higher in the GM-CSF group (1.90 vs 0.46 x 10(9)/l). The lymphocyte count was significantly higher in the GM-CSF than in the placebo group between days 10 and 15 after transplantation, but this difference was not associated with a higher incidence of graft-versus-host disease. There was no evidence that GM-CSF was associated with a greater incidence of leukaemic relapse. The GM-CSF group had lower haemoglobin concentrations and platelet counts and higher plasma urea, creatinine, and bilirubin than the placebo group. The duration of hospital stay was the same for both patient groups. Further studies are now indicated to assess the overall effect of GM-CSF on outcome after allogeneic bone-marrow transplantation.

Bone marrow transplantation--the Marsden experience.

Leukemic relapse remains a major problem after both autologous and allogeneic transplantation. In the single-arm ALL autograft study our results were very encouraging and suggest that Melph/TBI can produce disease-free survival results at least as good as with other conditioning regimens. The role of postautograft maintenance remains unclear, but we feel our results are sufficiently encouraging to justify a randomized study, particularly as we studied a group of patients with relatively poor prognoses. In our study comparing Cy and TBI with Melph and TBI in AML, we have shown a significant increase in antileukemic activity after transplantation following the latter conditioning regimen. The retrospective study of Melph/TBI in autologous versus allogenic transplantation suggested that in AML this antileukemic effect may derive from increased GvHD and is not present in the autologous setting. We hope that by increasing the intensity of our GvHD prophylaxis we can reduce the toxicity of Melph/TBI and preserve its antileukemia effect. Our experience with GM-CSF has been a little disappointing: despite facilitating neutrophil recovery, we were unable to demonstrate a clinical benefit in the treatment arm. We hope to further investigate the use of cytokine combinations in the transplant setting.

Therapy-induced drug resistance in a human leukemia line (LALW-2). A clinically relevant model.

A human leukemic T-cell line, LALW-2, established by xenografting in nude mice, has been maintained through 14 serial passages. The cells display consistent morphologic features, immunophenotype, and karyotypic aberrations (including an 11;14 translocation) and exhibit rearrangement of the T-cell receptor beta-chain gene. The growth rate of LALW-2 xenografts was differentially affected by drugs administered to host mice, the cells being resistant to cytotoxic agents (particularly methotrexate and doxorubicin) used in treatment of the donor patient. In short-term in vitro culture, LALW-2 cells exhibited extreme resistance to methotrexate and were also resistant to vincristine, vinblastine, dactinomycin, and doxorubicin. The findings differ from those obtained with laboratory-derived methotrexate or multidrug-resistant cell lines. The response of LALW-2 cells, in both the nude mouse model and in vitro, is consistent with acquisition of drug-resistance as a result of clinical treatment.