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Biomedical subjects

I M Franklin

Publications and source records attributed to I M Franklin.

At least 19 recordsLinked to original sources
PubMed2006

Immature monocytes from G-CSF-mobilized peripheral blood stem cell collections carry surface-bound IL-10 and have the potential to modulate alloreactivity.

Production of the anti-inflammatory cytokine IL-10 by monocytes has been implicated as a probable negative regulator of graft-versus-host disease (GvHD) in patients undergoing allogeneic stem cell transplants (SCT). Monocytes from G-CSF-mobilized peripheral blood stem cell (gmPBSC) collections have been reported to produce more IL-10 than unmobilized monocytes in response to proinflammatory factors such as LPS. Why this should occur is unclear. In this study, monocyte phenotype and IL-10 localization and release were investigated in PB mononuclear cells (MNC) from 27 healthy donors mobilized for allogeneic SCT and from 13 patients with hematological malignancies mobilized for autologous SCT. All isolates contained elevated total percentages of monocytes in comparison with unmobilized PB, a high proportion of which displayed an immature phenotype. Stimulation of gmPB MNC with an inflammatory stimulus [fixed Staphylococcus aureus cells (SAC)] induced rapid up-regulation of CD14, indicating conversion to mature status. Localization studies indicated that IL-10 was predominantly present, bound on the surface of CD64(+)/CD14(low/neg) immature monocytes. Inflammatory stimuli (LPS, polyinosinic:polycytidylic acid, or SAC) induced release of variable quantities of IL-10 from the cell surface. MNC, separated into surface IL-10-positive or -negative fractions, differed in their ability to stimulate alloreactivity in MLR, and IL-10(+) MNC induced significantly lower levels of proliferation than IL-10(-) MNC. Thus, the subset of immature monocytes carrying surface-bound IL-10 in gmPB has the potential to modulate alloreactivity and GvHD after allogeneic SCT through cell-to-cell contact and released IL-10.

Donor Selection↗
PubMed2004

A randomized study (WOS MM1) comparing the oral regime Z-Dex (idarubicin and dexamethasone) with vincristine, adriamycin and dexamethasone as induction therapy for newly diagnosed patients with multiple myeloma.

Whilst infusional vincristine, adriamycin and dexamethasone (VAD) is an effective treatment for patients with multiple myeloma (MM), administration may be complicated by line-associated infections and thromboses. The oral regime, Z-Dex (idarubicin and dexamethasone) has been shown to be efficacious in MM. We conducted a randomized study comparing Z-Dex with VAD as induction therapy in newly diagnosed MM patients. A total of 106 patients (median age, 56 years; range: 37-73; Durie-Salmon stage II/III) were randomized to receive four to six cycles of Z-Dex or VAD. Central line complications were reported in 38 patients on 57 cycles, primarily because of infection. Neutropenia (all grades) was more common in the Z-Dex arm (P = 0.009) although grade III/IV neutropenia was not significantly different between the treatment groups (P = 0.06). Infections (all grades) were more commonly seen in the VAD arm (P = 0.001) although grade III/IV infections were not significantly different between the two groups (P = 0.081). The responses to therapy (complete/partial response) in evaluable patients were: VAD 74% vs. Z-Dex 58%, with an estimated difference in response of 16% (95% CI -2-33, P = 0.075). VAD recipients (15%) suffered early treatment-related mortality compared with 12% of Z-Dex recipients. Overall, 45 patients have died: disease progression (Z-Dex n = 13, VAD n = 10), regimen-related toxicity (Z-Dex n = 2, VAD n = 2), infection (Z-Dex n = 0, VAD n = 3), other causes (Z-Dex n = 7, VAD n = 2), unknown (Z-Dex n = 3, VAD n = 2). This study demonstrated that Z-Dex might be a suitable oral alternative to VAD for treating newly diagnosed MM patients, although definitive evidence for equivalence is not provided.

Adult↗
PubMed2004

Immediate haemostasis with recombinant factor VIIa for haemorrhage following Hickman line insertion in acute myeloid leukaemia.

Bleeding following Hickman line insertion is not uncommon but can be life threatening, especially in the presence of coagulopathy and thrombocytopenia following chemotherapy. Treatment to control the bleeding can be challenging and treatment options are limited. We present our experience of a patient who had persisting haemorrhage immediately following Hickman line insertion for administration of chemotherapy for relapsed acute myeloid leukaemia. Haemostasis could not be achieved after FFP and platelet administration. A single dose of recombinant factor VIIa (rhFVIIa) stopped the bleeding immediately, avoiding the need for surgical intervention or line removal. Our experience indicates rhFVIIa may be an effective option for bleeding related to Hickman line insertion.

Acute Disease↗
PubMed2003

No strong relationship between mannan binding lectin or plasma ficolins and chemotherapy-related infections.

Chemotherapy causes neutropenia and an increased susceptibility to infection. Recent reports indicate that mannan-binding lectin (MBL) insufficiency is associated with an increased duration of febrile neutropenia and incidence of serious infections following chemotherapy for haematological malignancies. We aimed to confirm or refute this finding and to extend the investigation to the plasma ficolins, P35 (L-ficolin) and the Hakata antigen (H-ficolin). MBL, L-ficolin and H-ficolin were measured in 128 patients with haematological malignancies treated by chemotherapy alone or combined with bone marrow transplantation. Protein concentrations were related to clinical data retrieved from medical records. MBL concentrations were elevated compared with healthy controls in patients who received chemotherapy, while L-ficolin concentrations were decreased and H-ficolin levels were unchanged. There was no correlation between MBL, L-ficolin or H-ficolin concentration and febrile neutropenia expressed as the proportion of neutropenic periods in which patients experienced fever, and there was no relation between abnormally low (deficiency) levels of MBL, L-ficolin or H-ficolin and febrile neutropenia so expressed. Patients with MBL < or =0.1 microg/ml had significantly more major infections than no infections within the follow-up period (P<0.05), but overall most patients had signs or symptoms of minor infections irrespective of MBL concentration. Neither L-ficolin nor H-ficolin deficiencies were associated with infections individually, in combination or in combination with MBL deficiency. MBL, L-ficolin and H-ficolin, independently or in combination, did not have a major influence on susceptibility to infection in these patients rendered neutropenic by chemotherapy. These results cast doubt on the potential value of MBL replacement therapy in this clinical context.

Adolescent↗
PubMed2002

ETV6/AML1 fusion by FISH in adult acute lymphoblastic leukemia.

Dual-color interphase fluorescence in situ hybridization (FISH) with ETV6 and AML1 probes was used for the first time on a series of 159 adult patients with acute lymphoblastic leukemia (ALL), for detection of the t(12;21)(p13;q22) translocation. Seven patients (4.4%) were found, with 50-100% of positive cells, of whom one of two tested, proved negative for the fusion product by RT-PCR. Two of them, aged 43 and 50 years, are the oldest patients so far confirmed to have the translocation. Three who relapsed at 10, 11 and 24 months, suggest that adults may not enjoy the good short-term prognosis reported for t(12;21)-positive children. Thirty-one-negative cases had signal numbers differing from the two expected for each gene. In 15 cases these results were consistent with the karyotype. In nine cases with uninformative cytogenetics, the numbers were consistent with those for centromeres and indicated a hidden aneuploidy. Loss of ETV6 genes in two cases and AML1 amplification in three others were not suspected from the cytogenetics. In conclusion, FISH proved to be reliable in defining ETV6/AML1 positivity in this group of patients as well as providing valuable insights into negative cases.

Adolescent↗
PubMed2002

The storage and re-infusion of autologous blood and BM as back-up following failed primary hematopoietic stem-cell transplantation: a survey of European practice.

BACKGROUND: Traditionally, autologous BM or PBSC have been stored as a secondary source ('back-up') of hematopoietic stem cells (HSC) prior to allogeneic and autologous HSC transplantation. METHOD: We conducted an audit of a single transplant center practice for providing back-up HSC and compared this practice with other European centers. Laboratory records relating to the collection and re-infusion of consecutive HSC harvests were reviewed for 515 transplants (300 autologous and 215 allogeneic HSC transplants). RESULTS: In our experience, 2.3% (five of 215) of allogeneic HSC transplants required secondary HSC rescue for failure to engraft or graft failure (MUD, n = 2; un-manipulated sibling BMT, n = 1; T-cell depleted sibling BMT, n = 2). For autologous transplants, 4.7% (14 of 300) required rescue due to failure to engraft or late graft failure (ABMT for AML, n = 8; CD34+ cell selection/ex vivo expanded, n = 4; ABMT/PBSCT, n = 2). Among the European centers, 69.7% replied to a postal questionnaire, demonstrating that 81.4% and 45.6% of centers stored a secondary HSC source for manipulated and unmanipulated MUD BMT, respectively; 50% and 11.6% of centers stored a secondary source of HSC for manipulated and unmanipulated matched sibling BMT, respectively; 36.4% and 12.7% of centers stored HSC for manipulated and unmanipulated matched sibling PBSCT, respectively. In the autologous setting, 15.2% and 62.1% of centers stored back-up for unmanipulated and manipulated BMT, respectively and 19.5% and 68.5% stored back-up for unmanipulated and manipulated PBSCT, respectively, when myeloablative conditioning regimens were used. DISCUSSION: These data suggest that a small minority of patients require a secondary source of HSC rescue, most commonly in transplants with higher risk of graft failure. This is reflected in the practice across Europe of storing 'back-up' HSC. Guidelines should accommodate the need for storage of a secondary source of HSC only in those transplants associated with a higher risk of graft failure, especially in relation to graft engineering.

Blood Banks↗
PubMed2001

Suppression of IL-2-induced T cell proliferation and phosphorylation of STAT3 and STAT5 by tumor-derived TGF beta is reversed by IL-15.

IL-2 responses are susceptible to suppression by TGFbeta, a cytokine widely implicated in suppression of inflammatory responses and secreted by many different tumor cell types. There have been conflicting reports regarding inhibition of IL-2-induced STAT3 and STAT5 phosphorylation by TGFbeta and subsequent suppression of immune responses. Using TGFbeta-producing multiple myeloma tumor cells we demonstrate that tumor-derived TGFbeta can block IL-2-induced proliferation and STAT3 and STAT5 phosphorylation in T cells. High affinity IL-2R expression was required for the suppression of IL-2 responses as a novel CD25(-) T cell line proliferated and phosphorylated STAT3 when cultured with tumor cells or rTGFbeta1. Activating T cells with IL-15, which does not use the high affinity IL-2R, completely restored the ability of T cells to phosphorylate STAT3 and STAT5 when cultured with tumor cells. IL-15-treated T cells proliferated normally when cocultured with tumor cells or rTGFbeta1, whereas IL-2 responses were consistently inhibited. Preincubation with IL-15 also restored the ability of T cells to respond to IL-2 by phosphorylating STAT3 and STAT5, and proliferating normally in the presence of tumor cells. IL-2 pretreatment did not restore T cell function. IL-15 also restored T cell responses by T cells from multiple myeloma patients, and against freshly isolated bone marrow tumor samples. Thus, activation of T cells by IL-15 renders T cells resistant to suppression by TGFbeta1-producing tumor cells and rTGFbeta1. This finding may be exploited in the design of new immunotherapy approaches that will rely on T cells avoiding tumor-induced suppression.

Cells, Cultured↗
PubMed2001

HTLV antibody screening using mini-pools.

At the present time, the UK blood transfusion services do not screen blood donations for anti-HTLV. This presentation describes a pilot study to ascertain the feasibility of HTLV antibody screening using mini-pools and also provides an estimate of HTLV prevalence within our donor population in Scotland and Northern Ireland. The Abbott/Murex HTLV I/II GE80/81 ELISA was selected for the trial. Thirty confirmed HTLV positive library samples were tested at various dilutions and five were shown to be nonreactive at a dilution of 1:100. Residues of mini-pools (of up to 95 individual donations) prepared for HCV NAT testing were tested with the Abbott/Murex GE80/81 assay. Of 6666 mini-pools (equivalent to 570 609 donations) tested, six were repeatedly reactive. All six mini-pools were confirmed HTLV antibody positive by line immunoassay. Four were confirmed to be HTLV-I positive, one HTLV-II positive and one HTLV positive (unable to type). Dilutions (1:100) of the five HTLV "nonreactive" positive samples were included in each test plate and used to determine a grey-zone cut-off. Using this grey-zone system an additional six (0.09%) mini-pool samples gave repeatedly reactive grey-zone results, none of which were confirmed. The minimum Scottish/Irish HTLV donor prevalence was shown to be 1:95 000.

Blood Donors↗
PubMed1999

Transforming growth factor beta from multiple myeloma cells inhibits proliferation and IL-2 responsiveness in T lymphocytes.

Multiple myeloma (MM) is a cancer of plasma cells, characterized by profound suppression of host immune responses. Here we show that MM cell lines significantly suppress the proliferation, blasting, response to interleukin-2 (IL-2), and expression of CD25 by concanavalin A (Con A)-activated or allostimulated peripheral blood T lymphocytes. T cells arrest in the G1 stage of the cell cycle, and do not enter the IL-2 autocrine growth pathway. T cell inhibition was mediated by a soluble factor. MM cell lines did not produce IL-10 but did produce large amounts of transforming growth factor beta1 (TGF-beta1). T cells were assessed for their ability to respond to IL-2 when co-cultured with MM cells in the presence or absence of the TGF-beta inhibitor, TGF-beta latency-associated peptide (LAP). MM cells suppressed IL-2 responses but this inhibition was completely reversed by TGF-beta LAP. A CD25-, IL-2-dependent blast cell line was not inhibited by MM cells or rhTGF-beta, confirming the specificity of the inhibition mechanism for the IL-2 autocrine growth pathway. We conclude that MM cells suppress T cells in their entry into the autocrine IL-2/CD25 pathway and in response to IL-2, and that TGF-beta has a significant role to play.

Adjuvants, Immunologic↗
PubMed1998

Autologous transplantation in chronic myeloid leukaemia using peripheral blood stem cells.

Forty-three patients with chronic myeloid leukaemia in first chronic phase were recruited to study intensive chemotherapy (idarubicin plus cytarabine; IdAC) followed by collection of peripheral blood stem cells (PBSC) in the recovery phase. PBSC autografting was performed on 32 patients. One patient died during mobilization and three died following autograft. All procedural deaths occurred in patients who received IdAc more than a year from diagnosis. Nine further patients died, eight following progression of CML. 72% of transplanted patients showed a major cytogenetic response but most cases have returned to Philadelphia-positive haemopoiesis. 62% of autografted patients remain alive (median survival from diagnosis 52 months). Four of the 11 patients who did not receive a transplant remain in chronic phase.

Adult↗
PubMed1998

A comparative analysis of lipid-complexed and liposomal amphotericin B preparations in haematological oncology.

No comparative clinical information on the properties of lipid-associated amphotericin preparations is presently available. In this single-centre retrospective analysis over a 5-year period the indications, efficacy and toxicity of true liposomal amphotericin (AmBisome) were compared with a lipid complexed preparation (Abelcet). In a novel approach APACHE III scores were used in addition to neutrophil counts, disease status and additional immunosuppression to accurately assess the severity of illness in both groups and enable valid comparison. Overall, AmBisome at a median dose of 1.9 mg/kg/d was found to have similar clinical outcome to Abelcet at a median dose of 4.8 mg/kg/d. Nephrotoxicity and electrolyte abnormalities were similar in both groups. Rigors and febrile episodes were more common with Abelcet. Prospective randomized comparative trials are required to clarify the optimum dosages and therapeutic and economic issues associated with these agents.

Adult↗
PubMed1998

Evaluation and eligibility of HLA-identical sibling donors for stem cell/bone marrow donation.

Overall, the number of allogeneic transplants performed world-wide has not increased dramatically over the past 5 years. However, the proportion of allogeneic transplants undertaken using peripheral blood progenitor cells (PBPCs) has risen significantly. Currently, as part of an ethically approved trial, potential donors are seen, assessed and consented by physicians not caring directly for the recipients. Thirty-five potential sibling donors were seen and assessed for their willingness and fitness to donate for 28 patients. One donor opted to give bone marrow and the rest selected PBPC donation. Seven of these donors were found to have concurrent medical conditions. Due to poor venous access, one donor was advised to donate bone marrow and two others donated bone marrow due to an underlying condition. Four others were deemed unfit for donation. Donation of stem cells from bone marrow or peripheral blood is not a risk-free procedure; careful preassessment and counselling is mandatory especially when the age of prospective patients and therefore donors is increasing.

Adult↗
PubMed1998

Autografting as first line treatment for chronic myeloid leukaemia.

Interest in autografting for chronic myeloid leukaemia and its clinical relevance has revived in recent years. This followed observations that with various chemotherapeutic regimens it was possible to achieve, temporarily at least, peripheral blood and bone marrow that were Philadelphia negative. Bone marrow or peripheral blood progenitor cells could then be harvested and reinfused following a high dose procedure, hopefully eliminating any residual disease, and resulting in prolonged disease free survival. This ideal has not yet been successfully achieved with current strategies. Recent results indicate that eliminating residual disease with current chemotherapy is not normally achievable. The use of more sensitive technologies such as polymerase chain reaction has revealed persistent disease in most if not all apparently Philadelphia negative cases. This is confirmed by results where disease relapse occurs following transplant in these cases. Despite this, clinically relevant remissions are obtained and further trials are indicated. In this review present treatment is discussed and future strategies, using novel techniques as an adjunct to current treatment, are proposed that might improve on present results or even lead to the elusive goal of cure.

Bone Marrow Transplantation↗