Biomedical subjects

David C Linch

Publications and source records attributed to David C Linch.

40 records · Page 3Linked to original sources

PubMed2002

Influence of cell cycling and cell division on transendothelial migration of CD34+ cells.

The migration of haemopoietic stem and progenitor cells across endothelium lining bone marrow sinuses is a critical first step in the homing and successful engraftment of these cells. We have previously shown that freshly isolated mobilized peripheral blood CD34+ cells adhere to the endothelial surface but do not transmigrate unless activated by growth factors. The aim of this work was to examine the relationship between cell cycle progression, cell division and migration across endothelium. We now show that the enhanced migration of cytokine-activated cells is selective for cells which are in G0G1 phase of the cell cycle. Thus, the transmigrated population of CD34+ cells was enriched for cells in G0G1 phase, and sorted cells in G0G1 migrated more efficiently than those in S+G2M. Conversely, cells in S+G2M were more adherent to endothelium, a finding that may explain their reduced migration. Using the cytoplasmic dye, carboxyfluorescein diacetate succinimidyl ester, to track the divisional kinetics of CD34+ cells, we found that migration occurred preferentially in non-divided cells. Thus, although CD34+ cells require cytokine activation in order to migrate, cell division is not required for transmigration, which occurs optimally before cells enter S phase. The superior migratory ability of CD34+ cells in G0G1 phase of the cell cycle may have important implications for the homing and engraftment of ex vivo expanded cells.

Adult↗

PubMed2002

Respiratory virus infections in transplant recipients after reduced-intensity conditioning with Campath-1H: high incidence but low mortality.

Respiratory virus infections can cause serious morbidity and mortality after conventional allogeneic stem cell transplantation. However, the incidence and outcome of these infections after reduced intensity conditioning has not been reported. Between 1997 and 2001, 35 episodes of respiratory virus infections were noted in 25 of 83 transplant recipients conditioned with fludarabine, melphalan and Campath-1H, and 80% of them received early antiviral therapy. Parainfluenza virus (PIV) 3 was the commonest isolate (45.7%) followed by respiratory syncytial virus (37%). Patients with myeloma were more susceptible to these infections [odds ratio (OR) 4.1, P = 0.01] which were often recurrent in patients with severe acute or chronic graft-versus-host disease (GVHD) (OR 10.6, P = 0.03). Infection within the first 100 d (OR 5.0, P = 0.05) and PIV 3 (OR 9.2, P = 0.01) isolation were risk factors for developing lower respiratory infection. Although more than half of the episodes progressed to lower respiratory infection, the mortality was only 8%. This could have been due to early initiation of antiviral therapy, but the attenuation of pulmonary damage due to the reduced-intensity conditioning, low incidence of GVHD and, paradoxically, the low CD4+ T-cell subset in this setting might also have been contributory factors.

Adolescent↗

PubMed2002

Debate on the conservative and aggressive treatment options for the optimal management of indolent non-Hodgkin's lymphoma.

Indolent non-Hodgkin's lymphoma (NHL) is currently considered to be an incurable disease, with a median survival of 6-8 years. In the absence of a cure, the variety of therapeutic options available for patients with indolent NHL range from 'watchful waiting' to high-dose therapy (HDT) with autologous stem-cell transplantation (ASCT). There is no current consensus on standard treatment. Conventional chemotherapy is clearly not curative, and many clinicians prefer to delay chemotherapy until the patient develops overt symptoms that require treatment. On the one hand, long-term studies indicate that 'watchful waiting' has no effect on overall survival. On the other hand, aggressive treatment strategies, such as HDT with ASCT, may increase disease-free survival in some patients, particularly when used early in the treatment algorithm, but are also associated with potential toxicity. Thus the selection of therapy for each patient involves balancing the benefit of the treatment with any side effects and detriment to quality of life. The development of innovative therapies for indolent NHL, such as monoclonal antibodies with or without chemotherapy, requires a reassessment of the treatment choices. Good clinical responses and time to progression have so far been achieved in clinical trials of rituximab and other agents including radiolabelled antibodies, but in view of the long median survival of patients with indolent NHL, it will be some years before it can be conclusively demonstrated whether such treatments have an effect on the natural history of the disease or produce a cure. This issue raises an important question: outside the setting of a clinical trial, should patients be treated aggressively with therapies that do not yet have proven curative ability? This article considers the evidence and relative merits for the conservative approach to indolent NHL, where patients are treated according to symptoms in order to maintain a normal quality of life wherever possible, and for the aggressive approach, where the lymphoma is targeted soon after the diagnosis.

Antibodies, Monoclonal↗

PubMedDate not supplied

Clinical evidence of a graft-versus-Hodgkin's-lymphoma effect after reduced-intensity allogeneic transplantation.

BACKGROUND: In patients with multiply relapsed Hodgkin's lymphoma allogeneic stem-cell transplantation has been limited by prohibitive non-relapse-related mortality rates and by a lack of definitive evidence for a therapeutic graft-versus-tumour effect. Therefore, we aimed to assess the graft-versus-tumour effect of reduced-intensity allogeneic transplantation. METHODS: We undertook reduced-intensity transplantation in 49 patients with multiply relapsed Hodgkin's lymphoma, 44 (90%) of whom had progression of disease after previous autologous transplantation (median age 32 years [range 18-51], number of previous treatment courses was five [range 3-8], and time from diagnosis 4.8 years [range 0.6-4.8]). 31 patients had HLA matched donors who were related and 18 had donors who were unrelated. Median follow-up was 967 days (range 102-2232). The primary endpoints were engraftment, toxic effects, non-relapse-related mortality, incidence of graft-versus-host disease (GVHD), and the toxic effects of adjuvant donor-lymphocyte infusion. FINDINGS: All patients engrafted. Eight of 49 (16%) had grade II-IV acute GVHD and seven (14%) had chronic GVHD before donor-lymphocyte infusion. 16 (33%) patients received donor-lymphocyte infusion from 3 months after transplantation for residual disease or progression. Six (38%) of the 16 developed grade II-IV acute GVHD and five developed chronic GVHD. Nine (56%) showed disease responses after infusion (eight complete, one partial). Non-relapse-related mortality was 16.3% at 730 days (7.2% for patients who had related donors vs 34.1% for those with unrelated donors, p=0.0206). Projected 4 year overall and progression-free survival were 55.7% and 39.0%, respectively (62.0% and 41.5% for related donors). INTERPRETATION: These data show the potential for durable responses in patients who have previously had substantial treatment for Hodgkin's lymphoma. The low non-relapse-related mortality suggests the procedure could be undertaken earlier in the course of the disease.

Adolescent↗