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C D Williams

Publications and source records attributed to C D Williams.

At least 19 recordsLinked to original sources
PubMed2005

Analysis of outcome following allogeneic haemopoietic stem cell transplantation for myeloma using myeloablative conditioning--evidence for a superior outcome using melphalan combined with total body irradiation.

We have undertaken a retrospective multicentre analysis of 139 patients (median age 44.4 years) undergoing allogeneic haematopoietic stem cell transplantation (HSCT) for multiple myeloma using myeloablative conditioning. The majority of patients received total body irradiation (TBI) combined with either melphalan (56.9%) or cyclophosphamide (28.5%). Overall, transplant-related mortality (TRM) was 37.9% at 1 year and was not significantly different for patients receiving melphalan/TBI compared with cyclophosphamide/TBI. The overall complete remission (CR) rate, including patients in CR at the time of transplant, was greater for patients receiving melphalan/TBI (64.7%) compared with cyclophosphamide/TBI (47.2%)(P = 0.085). A significantly higher proportion of patients with continuing disease at the time of transplant achieved CR post-transplant following melphalan/TBI conditioning compared with cyclophosphamide/TBI (52.9% and 33.4% respectively, P = 0.009). Relapse/progression rates at 5 years were significantly lower for melphalan/TBI (36.7%) compared with cyclophosphamide/TBI (80.8%, P < 0.0001) and remained significant in multivariate analysis. This resulted in an overall survival at 5 years of 44.1% and 28.1% for melphalan/TBI and cyclophosphamide/TBI, respectively (P = 0.059). These results demonstrate that the type of conditioning for sibling allogeneic HSCT for myeloma has a major effect on transplant outcome.

Adult↗
PubMed2001

High-dose therapy and autologous stem-cell support for chemosensitive transformed low-grade follicular non-Hodgkin's lymphoma: a case-matched study from the European Bone Marrow Transplant Registry.

PURPOSE: To assess the outcome of high-dose therapy with autologous stem-cell support in patients with histologic transformation of low-grade follicular non-Hodgkin's lymphoma (NHL) and identify significant prognostic factors, as well as to compare survival of these patients with that of patients with matched low-grade and de novo high- or intermediate-grade NHL undergoing the same procedure. PATIENTS AND METHODS: Fifty patients with transformed low-grade NHL have been reported to the European Bone Marrow Transplant registry. Outcome from high-dose therapy and significant prognostic factors were analyzed. Their survival was also compared with that of 200 patients with matched low-grade NHL and 200 patients with matched de novo high- or intermediate-grade NHL by a case-matched analysis. RESULTS: The procedure-related death rate among the 50 transformed NHL patients was 18%. Overall survival (OS) and progression-free survival (PFS) rates were 51% and 30% at 5 years, respectively. Median PFS time was 13 months. Raised lactate dehydrogenase levels at transformation (P =.0031) was identified as the only adverse significant predictor of PFS on multivariate analysis. A subgroup of patients with residual chemosensitive disease who attained complete remission after high-dose therapy had the best outcome, with an OS at 5 years of 69%. A comparison with matched patients with low-grade disease and with de novo high- or intermediate-grade lymphoma showed no significant difference in OS (P =.939 and P =.438, respectively). CONCLUSION: Patients with chemosensitive transformed lymphoma should be seriously considered for high-dose therapy and autologous stem-cell support.

Adult↗
PubMed2001

In vivo CAMPATH-1H prevents GvHD following nonmyeloablative stem-cell transplantation.

BACKGROUND: We have investigated a novel nonmyeloablative conditioning regimen in 44 patients with hematological malignancies. The median patient age was 41 years. Many of the patients had high-risk features, including 19 patients with a previous failed transplant. METHODS: Recipient conditioning consisted of CAMPATH-1H 20 mg/day on Days -8 to -4, fludarabine 30 mg/m(2) on Days -7 to -3 and melphalan 140 mg/m(2) on Day -2. Thirty-six recipients received unmanipulated G-CSF mobilized PBSC from HLA identical siblings and eight received unmanipulated BM from MUD. GvHD prophylaxis was with CYA alone for 38 patients and CYA plus MTX for six sibling recipients. RESULTS: Forty-two of the 43 evaluable patients had sustained engraftment. Results of chimerism analysis using microsatellite PCR indicate that 18 of 31 patients studied were full donor chimeras, while the other patients were mixed chimeras in one or more lineages. At a median follow-up of 9 months (range, 3-29 months) 33 patients remain alive in CR, or with no evidence of disease progression. Seven patients relapsed or progressed post-transplant and four of them subsequently died. Four patients died from regimen-related complications. There were no cases of Grades III-IV acute GvHD. Only two patients developed Grade II acute GvHD and only one had chronic GvHD. The estimated probability of non-relapse mortality at 1 year was 11%.Results: Although longer follow-up is needed to establish the long-term remission rates, this study demonstrates that this nonmyeloablative preparative regimen is associated with durable engraftment, minimal toxicity and low incidence of GvHD.

Adolescent↗
PubMed2001

A prospective, randomized study of endometrial telomerase during the menstrual cycle.

The purpose of this study was to characterize telomerase activity during the menstrual cycle, focusing on the luteal phase. A total of 84 endometrial biopsy samples were obtained from 72 participants. Daily urinary LH testing (OvuQuick, Quidel) was used to establish the day of the LH rise, and participants were randomized to return during the secretory phase. Twelve women returned on the identical day during the luteal phase of a subsequent cycle to allow intercycle comparisons of telomerase activity. Telomerase activity was evaluated using a modified TRAP-eze (Intergen) detection protocol. At the time of each endometrial biopsy, serum estrogen and progesterone were measured. Proliferative phase endometrium showed high telomerase activity. At the onset of the luteal phase telomerase activity was high, but it decreased during the early luteal phase, disappeared by the midluteal phase (6 d after LH surge detected), and then rose to moderate levels in the late luteal phase beginning on luteal d 10. Serum progesterone levels were inversely related to telomerase activity. In conclusion, endometrial telomerase activity is dynamic: high during the proliferative phase but inhibited during the midsecretory phase of the menstrual cycle. The timing of expression coincides with the rise and fall of progesterone levels and the time period of maximal uterine receptivity for embryo implantation. This supports a relationship between sex steroid levels and telomerase regulation.

Adult↗
PubMed2000

In vivo CAMPATH-1H prevents graft-versus-host disease following nonmyeloablative stem cell transplantation.

A novel nonmyeloablative conditioning regimen was investigated in 44 patients with hematologic malignancies. The median patient age was 41 years. Many of the patients had high-risk features, including 19 patients with a previous failed transplant. Recipient conditioning consisted of CAMPATH-1H, 20 mg/day on days -8 to -4; fludarabine, 30 mg/m(2) on days -7 to -3; and melphalan, 140 mg/m(2) on day -2. Thirty-six recipients received unmanipulated granculocyte colony-stimulating factor-mobilized peripheral blood stem cells from HLA-identical siblings, and 8 received unmanipulated marrow from matched unrelated donors. GVHD prophylaxis was with cyclosporine A alone for 38 patients and cyclosporine A plus methotrexate for 6 sibling recipients. Forty-two of the 43 evaluable patients had sustained engraftment. Results of chimerism analysis using microsatellite polymerase chain reaction indicate that 18 of 31 patients studied were full-donor chimeras while the other patients were mixed chimeras in one or more lineages. At a median follow-up of 9 months (range 3 to 29 months), 33 patients remain alive in complete remission or with no evidence of disease progression. Seven patients relapsed or progressed post-transplantation, and 4 of them subsequently died. Four patients died of regimen-related complications. There were no cases of grades III-IV acute GVHD. Only 2 patients developed grade II acute GVHD, and only 1 had chronic GVHD. The estimated probability of nonrelapse mortality was 11%. Although longer follow-up is needed to establish the long-term remission rates, this study demonstrates that this nonmyeloablative preparative regimen is associated with durable engraftment, minimal toxicity, and low incidence of GVHD.

Adolescent↗
PubMed1998

p130, p107, and pRb are differentially regulated in proliferating cells and during cell cycle arrest by alpha-interferon.

We have determined how the phosphorylation of the retinoblastoma family (pRb, p107, and p130) is governed in individual cell cycle phases of Daudi B-cells during cell cycle exit triggered by alpha-interferon (alpha-IFN). alpha-IFN causes dephosphorylation of pRb and loss of p130 phosphorylated Form 3. However, the change in p130 phosphorylation in response to alpha-IFN occurs before dephosphorylation of pRb is complete because loss of p130 Form 3 occurs throughout the cell cycle prior to complete arrest in G1, whereas pRb is dephosphorylated only in G1. In contrast, p107 is dephosphorylated and is then depleted from cells as they exit the cell cycle. p130, predominantly in Form 1, and hypophosphorylated pRb bind an E2F DNA binding site; p130 complexes E2F-4, whereas pRb binds both E2F-4 and E2F-1. The phosphorylated forms of E2F-4 that bind to the E2F DNA site are different from hyperphosphorylated E2F-4, which predominates in primary hemopoietic cells in G0. We conclude that although cell cycle arrest induced by alpha-IFN may be mediated in part by formation of a complex containing p130 and E2F-4, alpha-IFN does not induce hyperphosphorylation of E2F-4, which characterizes primary hemopoietic cells in G0.

B-Lymphocytes↗
PubMed1998

A prospective study of transvaginal hydrosonography in the evaluation of abnormal uterine bleeding.

OBJECTIVE: The purpose of this study was to determine whether the intrauterine instillation of saline solution during transvaginal ultrasonographic imaging (hydrosonography) improves the diagnostic accuracy in detecting intrauterine abnormalities determined by direct visualization of the intrauterine cavity with either hysteroscopy or after hysterectomy. STUDY DESIGN: This study was a prospective, blinded study of 39 women referred with the diagnosis of abnormal uterine bleeding after failing medical management. A routine vaginal probe ultrasonographic examination was followed by a blinded transvaginal hydrosonography in patients proceeding to either hysteroscopy or hysterectomy. RESULTS: Twelve of the 39 patients had masses that impinged on the intrauterine cavity at hysteroscopy or hysterectomy. In 4 of the 12 patients with confirmed masses, an intrauterine lesion was detected by hydrosonography that was not seen on routine vaginal probe ultrasonography. In no case was an intrauterine mass detected by the hysteroscopy or after hysterectomy when hydrosonography indicated a normal intrauterine cavity. In 4 cases hydrosonography suggested that masses were present that were not confirmed at direct visualization. Although hydrosonography always recognized when intracavitary pathologic conditions existed in a patient, hydrosonography sometimes underestimated the number of intracavitary lesions present. CONCLUSIONS: Hydrosonography is a simple, minimally invasive, and effective tool to use in the evaluation of patients with abnormal uterine bleeding who have not responded to medical treatment. In no case did hydrosonography fail to indicate when pathologic conditions existed in a given patient, and a normal hydrosonography always indicated a normal intrauterine cavity at hysteroscopy or after hysterectomy. For these reasons hydrosonography is a sensitive tool to triage women with abnormal uterine bleeding to operative or conservative management.

Adult↗
PubMed1998

A case of EBV-associated lymphoproliferative disease following high-dose therapy and CD34-purified autologous peripheral blood progenitor cell transplantation.

A fatal case of EBV-associated lymphoproliferative disorder arising after a CD34-selected autologous peripheral blood stem cell transplant is reported in a patient with multiple myeloma in first plateau phase. It is suggested that this is likely to be a consequence of the accessory cell depletion associated with the CD34+ cell purification and it is recommended that a source of autologous T cells is stored before transplantation to be used if a severe opportunistic infection or EBV lymphoma arises post-transplantation.

Antigens, CD34↗
PubMed1998

Back-up bone marrow is frequently ineffective in patients with poor peripheral-blood stem-cell mobilization.

PURPOSE: To assess hematologic recovery and procedure-related mortality in patients who received high-dose therapy with stem-cell support, in whom the peripheral-blood stem-cell (PBSC) collection fails (CD34+ cells < 1 x 10(6)/kg). The predictive value of granulocyte-monocyte colony-forming cell (GM-CFC) measurements and the value of bone marrow obtained after PBSC collection failure was assessed. PATIENTS AND METHODS: The study group comprised 324 consecutive patients mobilized with granulocyte colony-stimulating factor (G-CSF) and cyclophosphamide (273 patients), G-CSF with other chemotherapy (37 patients), and G-CSF alone (14 patients). Between one and four aphereses were performed. RESULTS: In 51 of 324 patients, there was failure to obtain 1 x 10(6)/kg CD34+ cells. Twenty-three patients had greater than 1 x 10(5)/kg GM-CFC; 22 patients proceeded to high-dose therapy. Neutrophil recovery occurred within 21 days, but platelet independence was delayed (> 28 days) in eight patients. Of 28 patients with less than 1 x 10(5)/kg GM-CFC, six received high-dose therapy with PBSC alone and five had delayed engraftment. Twelve patients with less than 1 x 10(5)/kg GM-CFC received high-dose therapy supported by bone marrow collected after PBSC collection failure. Eleven patients were assessable for engraftment; four patients had slow (> 21 days) or delayed (> 28 days) neutrophil recovery and eight patients had delayed platelet recovery. In the group of patients who received less than 1 x 10(5)/kg GM-CFC, there were five procedure-related deaths. CONCLUSION: This study shows that delayed hematologic recovery is frequent if less than 1 x 10(6)/kg CD34+ cells are infused after high-dose therapy, particularly with GM-CFC less than 1 x 10(5)/kg. The procedure-related mortality in this latter group is high. In most patients whose PBSC collection contains less than 1 x 10(5)/kg GM-CFC, the use of bone marrow cells does not improve engraftment, which suggests that poor PBSC mobilization usually indicates poor marrow function.

Adolescent↗
PubMed1998

Effectiveness of cognitive-behavioral therapy for smokers with histories of alcohol dependence and depression.

OBJECTIVE: Alcohol dependence and major depression have been associated with heavy cigarette use and poor smoking-treatment outcomes. This preliminary study examined the efficacy of a mood management intervention for smoking cessation in abstinent alcoholics with a history of major depression. METHOD: Participants were 29 (15 female, 14 male) heavy smokers (mean cigs/day = 30.2), with an average of 6.8 years of continuous abstinence from alcohol and drugs, randomized to behavioral counseling (BC) (n = 16) or behavioral counseling + cognitive-behavioral mood management (CBT) (n = 13). A 2 x 5 repeated measures design was used to evaluate the effectiveness of the interventions on smoking outcome at baseline, posttreatment and at 1-, 3- and 12-month-follow-up. Self-reported smoking status was verified with biochemical (COa) and informant report. RESULTS: Verified self-report indicated that significantly more smokers in CBT quit by posttreatment (69.2%; 9 of 13) than in BC (31.3%; 5 of 16) (chi2 = 4.14, 1 df, p = .04). These abstinence rates remained unchanged at 1-month follow-up. At 3-month follow-up, differences in smoking abstinence rates were nonsignificant between CBT (46.2%; 6 of 13) and BC (25.0%; 4 of 16) conditions. However, at 12-month follow-up, significantly more participants in CBT were abstinent from smoking (46.2%; 6 of 13) than in BC (12.5%; 2 of 16) (chi2 = 4.07, 1 df, p = .04). CONCLUSIONS: The results suggest that interventions focused on managing negative mood may benefit these high-risk, comorbid smokers.

Adult↗
PubMed1997

Characterization of cell cycle status and E2F complexes in mobilized CD34+ cells before and after cytokine stimulation.

Mobilized peripheral blood progenitors (CD34+ cells) have been shown to be either in the G0 or G1 phase of the cell cycle. In this study, it is shown that they are small cells with low protein content suggestive of G0. Support for this is provided by showing that the principal E2F complex consists of hypophosphorylated p130, E2F-4, and DP-1. The E2F-4 is more highly phosphorylated than in quiescent T cells. In response to cytokines in vitro, the CD34+ cells start to enter G1 within 8 hours and enter S-phase at about 48 hours. As cells enter G1, E2F-4 is dephosphorylated to several hypophosphorylated forms and three new DNA-binding complexes appear, including one containing E2F-4, DP-1, and p107. We suggest that mobilized CD34+ cells may be maintained in G0 by p130, E2F-4, and DP-1 and the coordinate dephosphorylation of E2F-4 and hyperphosphorylation of p130 may be central to the initiation of proliferation.

Antigens, CD34↗
PubMed1997

Remodeling of junctional complexes during the development of the outer blood-retinal barrier.

BACKGROUND: The retinal pigment epithelium (RPE) forms the outer blood-retinal barrier by separating the neural retina from fenestrated capillaries in the choroid. The barrier depends upon tight junctions within the apical junctional complexes that bind neighboring cells. During development, permeability decreases as the apical junctional complex gradually matures. To investigate this process, the composition of the apical junctional complex was monitored during RPE development in chicken embryos. METHODS: Permeability was monitored by incubating freshly isolated RPE/choroid in medium containing horseradish peroxidase followed by histochemical staining and electron microscopy. The expression of the tight junction proteins, ZO-1 and occludin, was determined by immunofluorescence and immunoblotting. Development of the RPE apical junctional complex was to compared to the homologous complex that forms the outer limiting membrane of the neural retina. RESULTS: The apical junctional complex of the RPE was permeable to horseradish peroxidase until embryonic day 10-12. Two putative forms of ZO-1 had approximately the same molecular mass as mammalian ZO-1 and were present in the apical junctional complexes at different stages of development. We identified one form as ZO-1, because it was present in mature RPE and shared an epitope with the rodent isoforms, ZO-1 alpha+ and ZO-1 alpha-. The second form lacked this epitope but was identified by a polyclonal antibody to ZO-1. It was designated the ZO-1-like protein (ZO-1LP). On embryonic day 3, occludin and ZO-1LP were observed along the apical surface of the neuroepithelium that gave rise to the RPE and the neural retina. In the neural retina, occludin expression decreased just before inner segments were formed, but ZO-1LP expression continued in the outer limiting membrane throughout development. During RPE development, occludin expression was constant or increased slightly. By contrast, ZO-1LP was gradually replaced by ZO-1 and total ZO-1 immunoreactive proteins decreased more than 10x. CONCLUSIONS: A gradual change in the composition of the apical junctional complexes accompanied the period of barrier formation. In RPE, ZO-1 gradually replaced ZO-1LP, but the decrease in ZO-1 expression suggests its functions during junction formation are not directly related to junction permeability. By contrast, occludin was lost and ZO-1LP retained where an adherens junction forms the permeable, outer limiting membrane.

Animals↗
PubMed1997

Evaluation of clinical scale CD34+ cell purification: experience of 71 immunoaffinity column procedures.

Seventy-one mobilised PBSC collections were subject to CD34+ cell purification using the CEPRATE SC stem cell concentration system. The overall median purity of CD34+ cells was 69% (6-93%). CD34+ cell, and GM-CFC recoveries were 52% (8-107%) and 36% (3-118%). Purity was logarithmically related to the input percentage of CD34+ cells and starting requirements were established of 1% CD34 cell content for optimal purity and a minimum of 2 x 10(6)/kg CD34+ cells to ensure recovery of our minimum engraftment threshold of 1 x 10(6)/kg CD34+ cells. Reduction of the washing steps reduced non-specific cell losses and shortened the procedure but did not affect progenitor cell recovery. Purified CD34+ cells were reinfused following high-dose therapy in 35 patients. The median time to neutrophil recovery of 0.5 x 10(9)/l was 12 (10-23) days and to the attainment of platelet independence was 13 (7-100) days. The risks of delayed platelet recovery were related to the CD34+ cell dose infused and were identical to the risks when non-purified PBSC collections were used. In conclusion, purification of CD34+ cells using the CEPRATE device is reliable and the purified product results in prompt engraftment. The cell losses that occur do however restrict its use in many patients.

Adult↗
PubMed1997

The predominant E2F complex in human primary haemopoietic cells and in AML blasts contains E2F-4, DP-1 and p130.

The E2F family of transcription factors are thought to play an important role in the control of cell cycle progression. There is now also increasing evidence that some family members may act as oncogenes or tumour suppressor genes. The characterization of these proteins in human primary haemopoietic cells and acute myeloid leukaemia (AML) blasts may thus give an insight to the molecular mechanisms governing proliferation and leukaemogenesis in these cells. Therefore we analysed the expression of E2F-DNA binding activity and the constituent proteins found in the complexes in human primary haemopoietic cells of various lineages. We also studied blasts from 18 patients with acute myeloid leukaemia (AML). On electromobility shift assays (EMSA) a single E2F-DNA binding complex was detected in T cells, B cells and monocytes which was shown to contain E2F-4, DP-1 and p130, indicating that all quiescent haemopoietic cells have the same complex. Examination of 18 AML samples by EMSA revealed the presence of E2F binding and no gross abnormalities were detected. An E2F-4/p130 complex was detected in representative samples of all FAB types analysed. Thus abnormalities of E2F function are unlikely to play a primary pathogenic role in AML.

Blotting, Western↗