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Biomedical subjects

J M Goldman

Publications and source records attributed to J M Goldman.

At least 19 recordsLinked to original sources

The third International Congress on Myeloproliferative and Myelodysplastic Syndromes.

This meeting was convened by Richard T. Silver and co-chaired by Jerry L. Spivak. It was held from 27 to 29 October 2005 in Washington, DC. Thirty-one invited speakers from seven different countries participated in the conference, which was attended by more than 300 individuals from 23 countries. As in previous years, a clinical symposium for patients, held the day before the symposium, was sponsored by the Cancer Research and Treatment Fund, Inc., New York, NY 10021. This meeting report provides a summary of the five sessions prepared and highlighted by one of the session chairs. In addition to the formal presentations on the biology, clinical aspects and management of these diverse marrow stem cell disorders, there was considerable interest generated because of the availability of several new agents that have been recently approved. A special luncheon satellite symposium was devoted to the dramatic changes in the therapeutic options for the myelodysplastic syndromes, sponsored by MGI Pharma, Inc. The keynote address was presented by Dr. George Q. Daley from Harvard Medical School and the Children's Hospital Medical Center. He reviewed the molecular steps in the formation of the Philadelphia chromosome and some of the newly described mutations leading to resistance to chemotherapy (see Section 4).

Humans↗

Topical issues in unrelated donor haematopoietic stem cell transplants: a report from a workshop convened by the Anthony Nolan Trust in London - 2005.

Over more than three decades, The Anthony Nolan Trust (ANT) has provided an unrelated donor (UD) for over 4000 children and adults lacking a suitable family member donor, and has remained at the forefront of developments in haematopoietic stem cell transplantation (HSCT) and bone marrow register management. These three decades have seen major changes in clinical practice of UD-HSCT, including new indications, increased use of alternative haematopoietic cell sources, significant improvement of the outcome as a result of better support care, less-toxic conditioning regimens, and better donor selection, and expansion to older patients with higher comorbidities. In order to foster our goal of improving UD-HSCT availability and outcome in a progressively more complex clinical scenario, a new initiative from ANT was launched in 2005 to convene an experts workshop to address the topical issues in this field. Four consecutive panels addressed factors influencing donor selection and transplant outcome, the use of cord blood, regulatory and accreditation issues, and future developments in this field. This report summarizes the discussions held in this workshop, which will likely develop into a periodic event where transplant clinicians, scientists and registry members will meet to share their experience and vision in the field of UD-HSCT.

Donor Selection↗

The presence of a BCR-ABL mutant allele in CML does not always explain clinical resistance to imatinib.

The expansion of a leukemia clone bearing a Bcr-Abl kinase domain mutation is associated with acquired resistance to imatinib and may also predict disease progression in patients with Philadelphia-positive chronic myeloid leukemia (CML). Here we report results of pyrosequencing to quantitate the non-mutated and mutant alleles in 12 CML patients monitored over periods ranging from 11 to 58 months, and describe three contrasting kinetic patterns: Group 1 - in four patients total BCR-ABL transcript numbers remained high with the mutant allele predominating; Group 2 - in four patients the total number of BCR-ABL transcripts fell to low levels but the mutant allele predominated; and Group 3 - in four other patients the total level of transcripts remained high (n = 2) or fell (n = 2) but the mutant clone persisted at relatively low level. In Group 2 the mutant leukemia clone was presumably still relatively sensitive to imatinib but in Group 1 the leukemia could be classified as resistant. In Group 3 patients the imatinib sensitivity of the leukemia was variable. We conclude that a mutant clone does not necessarily have a proliferative advantage and its presence does not always account for resistance to imatinib. Other mechanisms underlie resistance in at least some patients.

Adult↗

An outbreak of tuberculosis in the South West of England related to a public house.

There had been a continuous decline in Mycobacterium tuberculosis infection (TB) during the last century until the trend plateaued in the mid-1980's and started to increase in the early 1990's in the United Kingdom (UK). In England and Wales the incidence of TB has increased by 11% between 1993 and 1998 with an overall incidence equal to 10.9/100,000 population. In the South West (SW) of England the incidence of TB is less than the UK average (4.6/100,000). We report an outbreak of TB in the SW of England which was based around a local public house. Sixteen patients received treatment and thirteen received chemo-prophylaxis. Using a rapid IS6 110- based PCR and Restricted Fragment Length Polymorphism Method, all mycobacteria isolated were shown to be identical, and all cultures were sensitive to the usual anti-mycobacterial drugs. All patients were white Caucasians and none were from high risk groups. Despite the absence of conventional close household contacts a significant number of secondary cases were detected. Possible links between TB cases should be considered even in areas of low prevalence.

Journal Article↗

Wegener's granulomatosis involving prostate.

We report a rare case of Wegener's granulomatosis involving the prostate in a 28-year-old man. The initial medical treatment was effective, but surgical intervention was required to manage late complications.

Adult↗

Monitoring patients in complete cytogenetic remission after treatment of CML in chronic phase with imatinib: patterns of residual leukaemia and prognostic factors for cytogenetic relapse.

We monitored BCR-ABL transcript levels by quantitative real-time PCR in 103 patients treated with imatinib for chronic myeloid leukaemia in chronic phase for a median of 30.3 months (range 5.5-49.9) after they achieved complete cytogenetic remission (CCyR). The patients could be divided into three groups: (1) in 32 patients transcript levels continued to decline during the period of observation (nadir BCR-ABL/ABL ratio 0.015%); in five of these patients BCR-ABL transcripts became undetectable on repeated testing, (2) in 42 patients the transcript levels reached a plateau and (3) in 26 patients transcript numbers increased and the initial CCyR was lost. Three patients were not evaluable. Patients who remained in CCyR for at least 24 months appeared to have a low risk of subsequent cytogenetic relapse. We conclude that the pattern of 'residual' disease after achieving CCyR on imatinib is variable: some patients in CCyR show a progressive reduction in the level of residual disease, some reach a plateau where transcript numbers are relatively stable and others relapse with Ph-positive metaphases.

Adolescent↗

Lymphoid transformation in a CML patient in complete cytogenetic remission following treatment with imatinib.

We describe here a patient with Philadelphia (Ph) chromosome-positive chronic myeloid leukemia who achieved a complete cytogenetic response following treatment with imatinib and then progressed abruptly to lymphoid blastic transformation. The sequence of events suggests that at least in some cases patients who respond well to imatinib may still harbor residual leukemia progenitor or 'stem' cells that are susceptible to acquisition of molecular events that underlie progression to advanced phase disease. The case highlights the need for molecular monitoring of responders and the need to develop strategies for reducing to a minimum or totally eradicating leukemia cells.

Aged↗

Efficacy of dual-specific Bcr-Abl and Src-family kinase inhibitors in cells sensitive and resistant to imatinib mesylate.

Monotherapy of chronic myeloid leukemia (CML) with imatinib mesylate has been cast into shadow by the evolution of clinical resistance during therapy. Resistance to imatinib can arise by multiple mechanisms including amplification or mutation of Bcr-Abl, and continuity of imatinib therapy is probably a poor option for either of these patient groups. Recently, however, a structurally distinct new class of drugs, the pyrido[2,3-d]pyrimidines, has been described, and these compounds are predicted to make different molecular contacts in the Abl kinase domain. These drugs potently target both the Bcr-Abl and Src-family kinase activities, both of which are thought to be relevant to survival of the leukemic cell. We asked whether these drugs could selectively induce cell death in murine cell line models of CML cells sensitive and resistant to imatinib by different mechanisms. We show that whereas the pyrido[2,3-d] pyrimidines are indeed highly potent in suppressing proliferation of Bcr-Abl-overexpressing imatinib-resistant cells, they are almost completely ineffective against cells expressing the T315I mutant. This implies that despite structural differences from imatinib, these drugs are unlikely to be useful in patients expressing this mutant Bcr-Abl protein, but may be effective in cases where selection of cells overexpressing the oncoprotein leads to refractoriness to imatinib.

Animals↗

Autologous stem cell transplantation normalizes abnormal bone remodeling and sRANKL/osteoprotegerin ratio in patients with multiple myeloma.

The osteoprotegerin (OPG)/receptor activator of NF-kappa B ligand (RANKL) system has a major role in the pathogenesis of bone disease in myeloma (MM). The effect of autologous stem cell transplantation (ASCT) on bone turnover in MM was evaluated in 51 patients (35M/16F). Markers of bone resorption (NTX, TRACP-5b), bone formation (bone-alkaline phosphatase (bALP), osteocalcin), OPG and sRANKL were measured pre- and every month post-ASCT. The median follow-up period was 12 months. Four patients were transplanted in CR, 44 were transplanted in PR and three patients had progressive/resistant disease. All patients received bisphosphonates both pre- and post-ASCT. At baseline the majority of patients had increased NTX, TRACP-5b levels, and sRANKL/OPG ratio, while markers of bone formation were strongly suppressed. ASCT produced a significant reduction of sRANKL/OPG ratio, with a concomitant decrease of NTX, and TRACP-5b levels, starting the second month post-ASCT. Bone formation markers, osteocalcin and bALP, started to increase after the 9th and 11th month post-ASCT, respectively, while the increase of OPG preceded this. These results provide biochemical evidence that ASCT normalizes the abnormal bone resorption in MM patients possibly through the decrease of RANKL/OPG ratio, while bone formation requires a longer period to return to normal.

Adult↗

Report on slide session, British Society for Haematology, 43rd Annual Scientific Meeting, Glasgow, 2003.

Seven patients who had a diagnostic problem were presented at the British Society for Haematology, Annual Scientific Meeting in 2003. The likely diagnosis was discussed on the basis of a synopsis of the history and blood film and trephine biopsy features and forms the basis of this report. Diagnostic problems dealt with included lymphoproliferative and myeloproliferative disorders and haemolytic anaemia.

Adult↗

Autologous stem cell transplantation in multiple myeloma: improved survival in nonsecretory multiple myeloma but lack of influence of age, status at transplant, previous treatment and conditioning regimen. A single-centre experience in 127 patients.

High-dose therapy with autologous stem cell transplantation (ASCT) has become the treatment of choice for symptomatic eligible patients with multiple myeloma (MM). We report our centre experience and analyse retrospectively the prognostic influence of pretransplant characteristics and transplant modalities on response and survival. A total of 127 MM patients (median age: 55.2 years) were transplanted between 1994 and 2001. In all, 69 patients had IgG, 28 IgA, 23 light chain, one IgD and six non secretory MM. At the time of autograft, 6% of patients were in complete remission (CR), 73% in partial remission (PR), 12% showed minor response to previous treatment and 9% had stable or refractory disease. Prior to autograft, 79% of cases had received only one line of chemotherapy and 21% two or more lines. All patients received PBSC support after conditioning with 200 mg/m(2) melphalan alone (100 patients) or melphalan and TBI (27 patients). We evaluated the influence of age (using as cutoff value the ages of 55, 60 and 65 years), type of MM, status pre- and post-ASCT, number of lines of previous regimens, time of ASCT from diagnosis, year of autograft, dose of reinfused CD34+ cells, plasma cell infiltration and beta(2)-microglobulin at diagnosis on overall (OS) and progression-free survivals (PFS) to define patients with better prognosis. Following ASCT, 15% of patients were in CR and 81% in PR, while only two patients progressed. Median OS and PFS from transplantation were 50.4 and 23.5 months, respectively. Median OS from diagnosis was 79.7 months. Transplant-related mortality was 2.3%. Low levels of beta(2)-microglobulin and the achievement of CR post-transplant correlated with longer PFS (P<0.03 and P<0.01, respectively). The median PFS was 36.1, 23.9, 21.1 and 16.4 months for nonsecretory, IgG, IgA and light chain subtypes, respectively. Age was not an important prognostic factor at a cutoff value of 55 or 60 years. We conclude that ASCT is a safe and effective procedure even in resistant cases. The outcome was independent of age, time from diagnosis, previous treatment and conditioning regimen, but there was a tendency for better survival in the nonsecretory patients.

Age Factors↗

The degree of matching at HLA-DPB1 predicts for acute graft-versus-host disease and disease relapse following haematopoietic stem cell transplantation.

The importance of matching for HLA-DPB1 in unrelated donor haematopoietic stem cell (HSC) transplantation is little understood. Most transplant centres do not, currently, prospectively match for DPB1, but emerging data show that DPB1 matching does play a role in determining outcome. We studied the impact of HLA-DPB1 matching on outcome in 143 recipients of T-cell depletion transplants, who matched with their respective unrelated donors (allelic level) at HLA-A, -B, -C, -DRB1 and -DQB1. Of those matched at DPB1, 47.2% (17/36) developed acute graft-versus-host disease (aGvHD) as compared to 66.3% (55/83) of those who were mismatched. This led to a 19.1% (95% CI 0.1-38.3%) increase in the chance of developing aGvHD in mismatched patients (P=0.049). Relapse of the original disease occurred in 51 recipients; 23 of 37 (62%) matched at both DPB1 alleles, 28 of 82 (34%) were mismatched at one or two DPB1 alleles. Thus, there was a significantly higher relapse rate (P=0.0011) in transplant recipients who matched at both DPB1 alleles. In conclusion, a donor/recipient DPB1 match was associated with a significantly lower incidence of aGvHD and a significantly higher incidence of disease relapse. This study provides further evidence for an immunogenic role of HLA-DPB1 in HSC transplants.

Acute Disease↗

Prognostic factors for patients with chronic myeloid leukaemia in chronic phase treated with imatinib mesylate after failure of interferon alfa.

We assessed clinical results in 145 patients with chronic myeloid leukaemia in chronic phase who satisfied criteria for interferon-alpha failure and were thus eligible for treatment with imatinib at the Hammersmith Hospital. We used univariate and multivariate analyses to develop a risk score based on features defined after treatment for 3 months. We identified a low neutrophil count and poor cytogenetic response (<35% Ph-negative marrow metaphases) at 3 months as principal independent predictive factors and incorporated them into a three-tier prognostic scoring system for individual patients. For patients in the low-, intermediate- and high-risk groups, the probabilities of survival at 24 months were 100, 82 and 40% (P<0.0001) and progression-free survival 100, 66 and 15% (P<0.0001), respectively. This Hammersmith prognostic scoring system was validated with an independent cohort of patients treated at another UK centre.

Adolescent↗

Alemtuzumab (Campath-1H) for treatment of lymphoid malignancies in the age of nonmyeloablative conditioning?

The anti-CD52 (Campath-1) monoclonal antibodies (Mabs) have a substantial history of use for controlling graft-versus-host disease in allogeneic bone marrow transplantation. Now, with the availability of a humanised form, alemtuzumab (Campath-1H), and the demonstration that this agent can reduce the tumour burden in B-CLL, a new niche may be found - as a potentially curative agent in which its tumour purging ability in vivo combines with its role as a conditioning agent in nonmyeloablative transplantation. Review of the literature shows that alemtuzumab has unique advantages as a method of depleting malignant lymphocytes, including those in patients resistant to conventional chemotherapy. Alemtuzumab can also be used in BMT for depletion of normal T and B lymphocytes of both the recipient and donor for prevention of graft rejection and GVHD. It allows good stem cell recovery with resultant rapid engraftment, has a low risk of EBV-triggered secondary malignancy and does not interfere with blood stem cell mobilisation. As a method of eliminating the malignant clone in B-CLL, alemtuzumab has shown remarkable efficacy in heavily pre-treated patients, a number of whom have progressed to autologous or allogeneic transplantation. Efficacy data are shown within the context of other transplantation data for B-CLL. These results indicate that the combination of tumour-depleting and immunosuppressive properties of alemtuzumab should be explored, with the hope of providing improved treatment options for elderly patients with advanced B-CLL or indolent lymphoma whose prognosis is too poor currently to allow treatment with traditional regimens of high-dose myeloablative chemotherapy.

Adult↗

Drug responses of imatinib mesylate-resistant cells: synergism of imatinib with other chemotherapeutic drugs.

Imatinib mesylate (STI571, Glivec, Gleevec) is a powerful inhibitor of the tyrosine kinase activity of Bcr-Abl, the oncoprotein responsible for chronic myeloid leukemia (CML). The drug shows great efficacy in chronic phase, but is less effective in maintaining hematologic remissions in blast crisis patients. Our group has previously described several cell lines made resistant to imatinib. We now examine the question of cross-resistance to other chemotherapeutic drugs used in CML. Four paired imatinib-sensitive/resistant CML cell lines were assessed by caspase-3 and MTS assays for their proliferative response to cytosine arabinoside (Ara-C), daunorubicin (DNR), homoharringtonine (HHT) and hydroxyurea (HU), either alone or in combination with imatinib. Primary blasts from advanced-stage CML patients refractory to imatinib therapy were studied by semi-solid media clonogenic assays. We found that these drugs are generally capable of major inhibition of proliferation of the CML cell lines, although differential responses to DNR and HHT were noted between some sensitive and resistant cell line pairs, implying that resistance to imatinib may confer a growth advantage under such conditions. The four drugs were also effective in preventing the formation of progenitor cell colonies from CML patients both before treatment with imatinib, and after relapse on the drug. Isobolographic analysis implied that these drugs will generally combine well with imatinib, and in some cases will be synergistic. We conclude that Ara-C, DNR or HHT, either alone or in combination with imatinib, are likely to be the best therapeutic alternatives in the management of patients who become resistant to imatinib monotherapy.

Antineoplastic Combined Chemotherapy Protocols↗

Cytological examination of the whole endobronchial brush in bronchoscopic diagnosis of lung cancer.

The combination of cytological and histological techniques has significantly increased the accuracy of fibreoptic bronchoscopy (FOB) in the diagnosis of lung cancer. We tested the hypothesis that cytological examination of material obtained from the whole endobronchial brush might increase the diagnostic yield in patients where conventional brush specimens were negative. Fifty patients who had undergone FOB for suspected lung cancer were studied prospectively. Bronchial lavage, bronchial biopsy and conventional brushing were performed. The whole endobronchial brush was then cut off the end of its wire and transported in a universal pot containing Shandon cytospin collection fluid. The material was dislodged from the whole brush using a vortex and the remaining fluid was centrifuged at 2,000 r.p.m. The fluid concentrate was used to maketwo cytopsin preparations. Papanicolaou stain was used. Fifty patients were studied, of which thirty-nine (78%) had endoscopicaly visible tumour. Of those, bronchial biopsy conventional brushing lavage and whole brush were positive for malignant cells in 31 (79.4%), 29 (74.3%), 21 (53.8%), and 16 (41%) of cases, respectively. A diagnosis of lung cancer was confirmed in 35 (89.7%) cases of endoscopicaly visible tumour. Conventional brushing was positive in two out of 11 (18.2%) cases with no visible tumour. Whole brush analysis was not positive in any of the cases with negative conventional brushings and was the least sensitive test in detecting malignancy Whole endobronchial brush analysis has no advantage in bronchoscopic diagnosis of patients with suspected lung cancer.

Biopsy↗

CD4(+) bias in T cells cloned from a CML patient with active graft versus leukemia effect.

BACKGROUND: The ability to generate a GvL response by infusion of donor leukocytes (DL) in patients following relapse after BMT is now well documented and has been demonstrated to be particularly effective in patients with CML. METHODS: We generated T-cell lines from a patient who was undergoing an active GvL response following withdrawal of immunosuppression for cytogenetic relapse of CML. Cryopreserved pre-transplant leukemic cells were used as stimulators, to generate T-cell lines and oligoclonal lines from the lymphocytes. In total 38 sub-lines were generated from different bulk cultures. The lines were tested for their proliferative and cytotoxic capability to patient pre-transplant leukemic cells, PHA-transformed lymphoblasts, allogeneic CML cells, and autologous and allogeneic B-LCL. RESULTS: Four of the cloned lines tested recognized the patient's pre-transplant leukemic cells. Specifically, two were both cytotoxic and proliferative in response to patient leukemic cells and two were cytotoxic only. Six clonal lines recognized PHA blasts only and were proliferative; one was specific for PHA blasts and CML cells. The sub-lines were phenotyped for cell-surface markers and all were CD4(+) CD8(-) CD 16/56(-). The proliferative response of the leukemia-specific clonal lines could be blocked with anti-MHC Class II MAbs. DISCUSSION: These data suggest that CD4(+) cells play a crucial role in mediating the GvL effect in CML patients. Our observations can be used to delineate strategies for enhancing and investigating the GvL effect in CML.

Bone Marrow Transplantation↗