Biomedical subjects

C Horton

Publications and source records attributed to C Horton.

At least 19 recordsLinked to original sources

PubMed2003

Thalidomide after allogeneic haematopoietic stem cell transplantation: activity in chronic but not in acute graft-versus-host disease.

Thalidomide was used to treat acute (n=21) or chronic (n=59) graft-vs-host disease (GVHD) in 80 haematopoietic stem cell allograft recipients after failure to respond to the combination of cyclosporine and corticosteroids with or without other agents. The median time to onset of acute GVHD was 11 days, and thalidomide was started at a median of 48 days post transplant. In addition to corticosteroids and cyclosporine, 13 patients had also received other agents before thalidomide. None of the patients responded and all died of acute GVHD. For chronic GVHD (limited in 13, extensive in 46), thalidomide was started at a median of 385 days post transplant. In addition to corticosteroids and cyclosporine, 34 patients received azathioprine concomitantly. In all patients, thalidomide was added to the ongoing immunosuppressive regimen. The median duration of therapy with thalidomide was 60 days (range, 11-1210; <2 weeks in 11). In total, 13 patients (22%) had complete response, eight (14%) partial response and 38 (64%) no response. Response rates were comparable for limited (39%) and extensive (33%) chronic GVHD. At a median of 53 months, 19 patients are alive, 13 without evidence of chronic GVHD. Survival was significantly better in patients who responded to thalidomide. The principal causes of death were progressive chronic GVHD (n=29) and relapsed leukaemia (n=7). In conclusion, thalidomide has no activity in acute GVHD, but has some activity in chronic GVHD in combination with other agents.

Acute Disease↗

PubMed2002

Collection of peripheral blood stem cells in newly diagnosed myeloma patients without any prior cytoreductive therapy: the first step towards an 'operational cure'?

We have shown that primary therapy with non-myeloablative (140 mg/m(2)) high-dose melphalan (HDM) without hematopoietic support results in high response rates in untreated myeloma and very long-term survival of some patients. This study was designed to see if sufficient CD34 (+) cells can be harvested at presentation in newly diagnosed patients to administer myeloablative HDM (200 mg/m(2); HDM200) with autograft as primary therapy. This may improve outcome by rapid achievement of complete remission (CR) and possible avoidance of late myelodysplasia as a consequence of non-transplant induction chemotherapy. Thirty untreated patients received 1 g/m(2) methylprednisolone daily (days 1-6) and 12-16 micro g/kg G-CSF daily (days 3-6), and underwent leukapheresis on days 6 and 7. The median CD34(+) cell yield was 1.31 x10(6)/kg (range, 0.23-5.63), and was > or =1 x10(6)/kg in 73%. Cell yields were significantly lower than in 82 historical controls apheresed after completion of induction chemotherapy (median 2.16 x 10(6)/kg), and improved in patients who were apheresed again after induction chemotherapy. Three patients received primary therapy with HDM200 and autograft using these cells and attained CR. We conclude that it is possible to harvest stem cells in three-quarters of untreated myeloma patients. Increasing the number of apheresis procedures is needed to improve the number of CD34(+) cells collected.

Adult↗

PubMed2001

Glomerular filtration rate prior to high-dose melphalan 200 mg/m(2) as a surrogate marker of outcome in patients with myeloma.

We correlated age and body surface area corrected glomerular filtration rate (GFR) at the time of high-dose melphalan (HDM) administration with treatment-related toxicity (TT), time to disease progression and survival. Between 8/85 and 6/98, 144 newly diagnosed myeloma patients with a median age of 53 years (range, 31-72) received infusional chemotherapy with vincristine, doxorubicin and methylprednisolone, with/without cyclophosphamide or verapamil, followed by HDM 200 mg/m(2)and stem cell rescue. An additional patient received HDM at diagnosis. GFR was below normal in 38 patients (26%). At presentation, patients with low GFR at the time of HDM had higher serum creatinine, beta(2)M, stage III disease, calcium and Bence-Jones proteinuria. Toxic deaths post-HDM were similar in both groups (2/38 (5%) vs. 4/107 (4%)), though patients with low GFR had more oral mucositis (P< 0.0001), diarrhoea (P = 0.005) and infections (P = 0.04). The response and relapse rates of the 2 groups were not substantially different, but the median overall survival (OS) was significantly shorter in patients with low GFR (5.1 vs 7.5 years, P = 0.015). Multivariate analysis showed that a normal GFR and being in CR at the time of HDM were predictive of longer OS. We conclude that in context of high-dose chemotherapy for myeloma, dose of melphalan should not be modified in patients with low GFR and that early intensive treatment at relapse may improve results in patients with abnormal renal function.

Adult↗

PubMed2001

Comparison of new patients with Bence-Jones, IgG and IgA myeloma receiving sequential therapy: the need to regard these immunologic subtypes as separate disease entities with specific prognostic criteria.

Of the 61 newly diagnosed patients with Bence-Jones (BJ) myeloma presenting to our centre between May 1986 and December 1997, 53 received sequential therapy (ST) comprising infusional chemotherapy (IC) followed by high-dose therapy and autotransplantation with interferon-alpha2b maintenance. The outcome was compared with 153 IgG and 39 IgA similarly treated myeloma patients. Response to IC and high-dose was comparable between the three subtypes but a significantly higher proportion of patients with BJ myeloma failed to receive high-dose compared to IgG (P = 0.003) and IgA (P = 0.04) myeloma. Median overall survival (OS) of patients with BJ myeloma (2.8 years) and event-free survival (EFS, 1.2 years) was significantly shorter than for patients with IgG myeloma (4.5 years, P = 0.03 and 2.1 years, P = 0.03, respectively). However, among those patients who achieved complete remission there was no difference in OS and EFS between IgG and BJ myeloma. In distinction to IgG myeloma where age and beta2M were significant, Cox analysis on presentation features identified performance status and urine total protein as having significant impact on OS. We conclude that achieving CR is an important treatment aim in patients with BJ myeloma, conferring a similar outlook on survival as in patients with the IgG subtype, and there is a need to consider different subtype-specific staging systems when evaluating the results of published or ongoing therapeutic trials.

Adult↗

PubMed2001

The implication of compromised renal function at presentation in myeloma: similar outcome in patients who receive high-dose therapy: a single-center study of 251 previously untreated patients.

The purpose of the study was to determine the role of sequential therapy (ST) in new patients with myeloma presenting with renal dysfunction (RD): serum creatinine >140 micromol/L (1.6 mg/dL). Between April 1985 and June 1998, 251 patients, 59 (23%) with RD were entered into a ST program comprised of infusional chemotherapy (IC) with VAMP/C-VAMP (vincristine, doxorubicin, and methylprednisolone with/without cyclophosphamide) followed by autologous transplantation and interferon maintenance. The median overall survival (OS) of 251 patients from the start of IC was 4.2 yr with the RD group faring significantly poorer (median 2.5 yr) than those with no renal dysfunction (NRD; median 4.6 yr; p = 0.0025). Mortality during the first 100 d of IC was significantly higher in patients with RD (11/59; p = 0.01) compared to patients with NRD. In patients consolidated with high-dose therapy, the OS and event-free survival (EFS) were not significantly different between the two groups. Cox analysis of the variables at presentation failed to show RD as a factor influencing outcome, but it showed that patients with beta-2-microglobulin (beta2M) > or = 3.7 (p < 0.0001), age > or = 52.5 yr (p = 0.002), performance status (PS) > or = 2 (p = 0.005) and patients with light-chain myeloma (p = 0.03) had a significantly shorter OS, beta2M > or = 3.7, PS > or = 2, and light-chain myeloma were predictive of shorter EFS. The study shows that with modern intensive schedules of treatment, renal disease at presentation in isolation does not compromise outcome.

Adult↗

PubMed2000

Chronic graft versus host disease is associated with long-term risk for pneumococcal infections in recipients of bone marrow transplants.

Incidences of and risk factors for Streptococcus pneumoniae sepsis (SPS) after hematopoietic stem cell transplantation were analyzed in 1329 patients treated at a single center between 1973 and 1997. SPS developed in 31 patients a median of 10 months after transplantation (range, 3 to 187 months). The infection was fatal in 7 patients. The probability of SPS developing at 5 and 10 years was 4% and 6%, respectively. Age, sex, diagnosis, and graft versus host disease (GVHD) prophylaxis did not influence the development of SPS. Allogeneic transplantation (10-year probability, 7% vs 3% for nonallogeneic transplants; P =.03) and chronic GVHD (10-year probability, 14% vs 4%; P =.002) were associated with significantly higher risk for SPS. All the episodes of SPS were seen in patients who had undergone allograft or total body irradiation (TBI) (31 of 1202 vs 0 of 127; P =.07). Eight patients were taking regular penicillin prophylaxis at the time of SPS, whereas 23 were not taking any prophylaxis. None of the 7 patients with fatal infections was taking prophylaxis for Pneumococcus. Pneumococcal bacteremia was associated with higher incidences of mortality (6 of 15 vs 1 of 16; P =.04). We conclude that there is a significant long-term risk for pneumococcal infection in patients who have undergone allograft transplantation, especially those with chronic GVHD. Patients who have undergone autograft transplantation after TBI-containing regimens also appear to be at increased risk. These patients should receive lifelong pneumococcus prophylaxis. Consistent with increasing resistance to penicillin, penicillin prophylaxis does not universally prevent SPS, though it may protect against fatal infections. Further studies are required to determine the optimum prophylactic strategy in patients at risk. (Blood. 2000;95:3683-3686)

Adolescent↗

PubMed2000

Allogeneic blood and bone-marrow stem-cell transplantation in haematological malignant diseases: a randomised trial.

BACKGROUND: Autologous transplantation with peripheral blood stem cells (PBSC) results in faster haematopoietic-cell repopulation than with bone marrow. We prospectively compared bone marrow and PBSC for allogeneic transplantation. METHODS: Adult HLA-identical sibling donors provided bone marrow and lenograstim-mobilised PBSC. 39 patients with malignant haematological disorders were infused with either bone marrow (n=19) or PBSC (n=20) after standard conditioning regimens in a double-blind, randomised fashion. The identity of the infused products for all patients remained masked until 1 year after the last patient had received transplantation. FINDINGS: The PBSC group had significantly faster neutrophil recovery to 0.5x10(9)/L (median 17.5 vs 23 days, p=0.002), and platelet recovery to 20x10(9)/L (median 11 vs 18 days, p<0.0001) and to 50x10(9)/L (median 20.5 vs 27 days, p=0.02) than the bone-marrow group. PBSC patients were discharged from hospital earlier than were bone-marrow patients (median 26 vs 31 days, p=0.01). At 4 weeks after transplantation, absolute lymphocytes (0.48 vs 0.63, p=0.08) and CD25 cells (0.04 vs 0.08, p=0.007) were higher in the PBSC group, and the proportion of patients with absolute lymphopenia (74% vs 33%, p=0.03) and CD4 lymphopenia (59% vs 24%, p=0.05) was significantly higher in the bone-marrow group. There was no significant difference in the occurrence of acute or chronic graft-versus-host disease and overall survival. The probability of relapse was significantly higher in the bone-marrow group than in the PBSC group (p=0.01); all five relapses occurred among bone-marrow recipients. INTERPRETATION: Our small study indicates that PBSCs are better than bone marrow for allogeneic transplantation from HLA-identical siblings in terms of faster haematopoietic and immune recovery, and have the potential to reduce disease recurrence.

Adult↗

PubMed2000

Melphalan/TBI is not more carcinogeneic than cyclophosphamide/TBI for transplant conditioning: follow-up of 725 patients from a single centre over a period of 26 years.

As there is concern regarding the high carcinogenic potential of melphalan (Mel), 725 patients with haematological malignancies who received allogeneic (n = 714) or syngeneic (n = 11) transplants over the last 26 years were followed-up to evaluate if melphalan was more likely to result in secondary malignant neoplasms (SMNs) than cyclophosphamide (Cy). Three hundred and ninety-five were treated with Cy/TBI and 330 with Mel/TBI. Twelve patients developed non-haematological SMN. Median time to develop a SMN was 7 years (range 2-17 years). Age-adjusted rate was significantly higher than in the general population (observed 12 expected 1.2, risk 10; P < 0.0001). The cumulative overall risk of developing a SMN at 2, 5, 10 and 15 years post transplant was 0.4% (95% CI 0.1-2.6%), 1.7% (95% CI 0.6-4.4%), 6.4% (95% CI 2.8-10.8%) and 6.6% (95% CI 3.4-12.4%), respectively. Even though age-adjusted rates were higher than the general population melphalan/TBI was not associated with higher age-adjusted risk than Cy/TBI (increased risk 7.9 vs 11.4; P = NS). The cumulative overall risk of SMNs was not different with CY/TBI or Mel/TBI (8/393 vs 4/363; 10 year risk 4.4%, 95% CI 1.8-10.6 vs 8.4%, 95% CI 2.9-22.9; P = NS). The risk was significantly higher with use of additional cranial or cranio-spinal irradiation (17.5% vs 2.7% at 10 years; P = 0.0241). Transplants for acute lymphatic leukaemia resulted in a higher incidence of SMNs than did transplants for other diseases (ALL: 17.4%, 95% CI 6.3-42.6%; other diseases: 3.4% (95% 1.3-8.5%, P = 0.0469). The risk of SMN for patients with chronic GVHD was 8.4% (95% CI 3.7-18.7%) as compared to 3.5% (95% CI 1-11.1%) for patients without chronic GVHD (P = NS). No factor was associated with independently increased risk in multivariate analysis. Use of melphalan and TBI for transplant conditioning does not appear to be associated with higher risk of second malignant neoplasms than cyclophosphamide and TBI.

Adolescent↗

PubMed2000

Comparison of marrow and blood cell yields from the same donors in a double-blind, randomized study of allogeneic marrow vs blood stem cell transplantation.

Forty healthy adult donors underwent marrow (BM) as well as peripheral blood (PBSC) stem cell collections for their HLA-identical adult siblings with hematologic malignancies. BM was harvested on day 1 (target 3 x 108 nucleated cells/kg, 10 microg/kg lenograstim (glycosylated G-CSF) administered on days 2-6, and a single leukapheresis performed on day 6. The blood volume processed was the higher of 200% donor blood volume or 10 liters. The total nucleated cell (TNC) yields from PBSC were 1.1- to 4.3-fold higher than BM (median 7.0 vs 3.1 x 10(8)/kg, P < 0.0001). Although BM contained a higher proportion of CD34+cells (1.3% vs 0.7%, P < 0. 0001) and a comparable proportion of CD3+ cells (median 29% vs 26%, P = 0.4), the absolute numbers of CD34+ and CD3+ cells and their subsets were several times higher in PBSC. There was a poor correlation between BM and PBSC CD34 and TNC numbers, but a significant correlation between BM and PBSC CD3 numbers. Only five of 40 BM harvests contained >/=2 x 10(6) CD34+ cells/kg compared with 35 of 40 PBSC harvests (P < 0.0001). We conclude that the numbers of progenitor and immunocompetent cells in PBSC are several times higher than in BM. It is possible to collect adequate numbers of progenitor cells from blood after lenograstim stimulation more frequently than from marrow, and donors yielding low quantities of progenitor cells from BM usually deliver better quantities from PBSC. Bone Marrow Transplantation (2000) 25, 501-505.

Adjuvants, Immunologic↗

PubMed2000

The role of autologous transplantation in patients with multiple myeloma aged 65 years and over.

Autologous stem cell transplantation after high-dose melphalan for the treatment with multiple myeloma has resulted in prolonged progression-free survival and overall survival in patients under 65 years. We have examined the role of autologous transplantation in 17 patients with multiple myeloma over 65 years at our centre using a matched pair analysis with younger patients. The median age of this cohort of patients over 65 years was 67 years (65-74) and their outcome and transplant-related morbidity was compared with 17 younger pair mates with a median age of 55 years (31-64). Sixteen patients received high-dose melphalan, and one received busulphan with autologous stem cell rescue. The high-dose therapy was well tolerated in both elderly patients and the matched pairs, with comparable time to recover neutrophils and platelets. Treatment-related mortality also did not differ significantly in both the groups. Median overall survival of the elderly patients was 3.59 years similar to 3.01 years of the pair mates (P = 0.92). Autologous stem cell transplantation after high-dose melphalan conditioning was equally well tolerated in groups of patients above and below 65 years. There was no difference in relapse rate, OS and myelotoxicity in both the groups. These findings suggest that advanced age should not be an exclusion criterion from autologous transplant programmes. Bone Marrow Transplantation (2000) 25, 533-539.

Adult↗

PubMed2000

Autologous bone marrow transplantation for childhood acute lymphoblastic leukaemia in second remission - long-term follow-up.

From 1984 to 1996, 31 consecutive children without sibling donors, aged 5-19 years (median 8) with acute lymphoblastic leukaemia (ALL) in second complete remission (CR), received unpurged autologous bone marrow transplantation (ABMT) after melphalan and single fraction total body irradiation (TBI). ABMT was performed using fresh unmanipulated marrow harvested after standard reinduction and consolidation therapy 2-11 months (median 5) after relapse. With a median survival of 2.9 years the probability of survival for all patients in continuing second CR was 45.1% (95% CI, 24%-62%) after 5 years. Regimen-related and non-leukaemia mortality was 7% (95% CI, 2%-26%). The longest time to second relapse from ABMT was 3.1 years. Pituitary and gonadal dysfunction requiring hormonal replacement therapy occurred in the majority of long-term survivors. Twelve patients developed cataracts. ABMT with melphalan/single fraction TBI has proved an effective anti-leukaemia treatment with low regimen-related mortality but significant long-term morbidity. The current approach of allogeneic BMT from an unrelated donor when no sibling donor is available, following conditioning with cyclophosphamide/ fractionated TBI has resulted in a reduced relapse rate and improved short-term overall survival in the treatment of relapsed childhood ALL. However, long-term results are awaited.

Adolescent↗

PubMed2000

Acute lymphoblastic leukaemia-type intensive chemotherapy to eliminate minimal residual disease after high-dose melphalan and autologous transplantation in multiple myeloma - a phase I/II feasibility and tolerance study of 17 patients.

Aiming to target the minimal residual disease in patients with multiple myeloma, a phase I/II single centre study was undertaken for feasibility and tolerance of intensive acute lymphoblastic leukaemia consolidation chemotherapy (ALL-IC) as part of a strategy for post-transplant consolidation targeted at pre-B cells. Seventeen newly diagnosed patients with myeloma (median age 55 years; 30-65) were initially treated with courses of infused cyclophosphamide, vincristine, adriamycin and methylprednisolone (C-VAMP) followed by melphalan 200 mg/m2(HDM) and peripheral blood stem cell rescue (PBSC). Forty-seven percent were in CR and the rest in PR after HDM. ALL-IC consisted of vincristine, daunorubicin, etoposide, cytarabine, 6-thioguanine and prednisolone given over 5 days. All patients became neutropenic (<0.5 x 109/l) at a median of 10 days (4-18) and one of the 17 patients (5.8%) died 15 days post ALL-IC of sepsis. A further four have died of relapse with an overall survival (OS) of 67% at 4 years. Two of nine patients in PR at the time of ALL-IC achieved CR. Matched-pair analysis of 34 control patients shows no difference for OS and event-free survival between ALL-IC and controls. We conclude that ALL-IC given to myeloma patients after HDM/PBSC is as safe as when used in ALL and warrants further assessment in randomised trials for myeloma.

Adult↗

PubMed2000

A low CD34+ cell dose results in higher mortality and poorer survival after blood or marrow stem cell transplantation from HLA-identical siblings: should 2 x 10(6) CD34+ cells/kg be considered the minimum threshold?

We studied the effect of the CD34+ cell dose on transplant-related mortality (TRM) and survival in 39 patients randomized to receive lenograstim-mobilized PBSCT (n = 20) or BMT (n = 19) from HLA-identical siblings. Both marrow and blood were harvested, and one infused in a double-blind fashion. The median nucleated (7.0 vs 3.2 x 10(8)/kg; P < 0.0001), CD34+ (3.7 vs 1.5 x 10(6)/kg; P = 0.002), CFU-GM (42 vs 19 x 10(4)/kg; P = 0.002), and CD3+ (1.9 vs 0.3 x 10(8)/kg; P < 0.0001) cell doses with PBSCT were higher. Thirteen patients (6 BMT and 7 PBSCT) experienced TRM at 15-733 days (median 57); 10 of 20 receiving <2 x 10(6) CD34+ cells/kg compared with three of 19 receiving > or =2. Eight of 20 patients receiving <2 x 10(6) CD34+ cells/kg are alive compared with 14 of 19 receiving > or =2. In Cox analysis, CD34+ cell dose > or =2 x 10(6)/kg was associated with lower TRM (RR 0.2, P = 0.01), and higher overall (RR 3.7, P = 0.01) and event-free (RR 3.2, P = 0.02) survival. Other cell populations and the source of stem cells did not affect TRM or survival. We conclude that 2 x 10(6) CD34+ cells/kg may be the ideal minimum cell dose for allogeneic transplantation although lower doses do not preclude successful therapy. Since the likelihood of obtaining this threshold CD34+ cell number is significantly greater from blood than marrow, PBSCT may be preferable to marrow for allografts from HLA-identical siblings.

Adolescent↗

PubMed2000

The effects of a pediatric unilateral inguinal hernia clinical pathway on quality and cost.

BACKGROUND/PURPOSE: The purpose of this study is to discover whether a pediatric inguinal hernia surgical clinical pathway (CP) reduces the frequency of wound infections, return visits, times associated with surgical repair, or costs. METHODS: A multidisciplinary team developed the inguinal hernia surgical clinical pathway. Healthy children greater than 50 weeks gestational age who required unilateral hernia repair were considered for the study. Two groups were formed: (1) an intervention group selected randomly (n = 46, CI = 95%, power = .80) from patients enrolled from November 1996 through April 1997, and (2) a retrospective cohort control group (n = 46) matched to each intervention patient by age, gender, and medical history. Analysis of variance and chi2 testing were used to test for significant differences between the 2 groups in postoperative wound infections, readmission and emergency department return visits within 72 hours, times associated with surgical repair, and costs. RESULTS: There were no significant differences in postoperative wound infections, times associated with surgical repair, or readmission rates within 72 hours. Total cost significantly decreased, by 10% (P< or = .05), for pathway patients ($982 v $880). CONCLUSION: These results show that the use of a pediatric inguinal hernia surgical clinical pathway is associated with reduced cost while maintaining quality of care.

Child, Preschool↗

PubMed2000

Disease features in acute myeloid leukemia with t(8;21)(q22;q22). Influence of age, secondary karyotype abnormalities, CD19 status, and extramedullary leukemia on survival.

Over a period of 14 years, 50 patients (12 children and 38 adults) of whom 46 had acute myeloid leukemia (AML) and 4 had myelodysplastic syndrome characterized by the t(8;21)(q22;q22) translocation were referred to the Royal Marsden Hospital. The clinicopathological features of these cases were analyzed to determine the influence of age, secondary karyotype abnormalities, and expression of the lymphoid marker CD19 on event free survival, and presence of extramedullary leukemia on overall survival. They were treated with a variety of chemotherapy protocols and some had bone marrow transplantation. There appeared to be no difference in survival between children (age <17 years) and adults (age >16 years). Out of the 50 cases, 16 (32%) had the (8;21) translocation alone, 17 (34%) had additional loss of a sex chromosome and the remaining 17 (34%) had other karyotype abnormalities of which deletion or translocation of the long arms of a #9 was most common (observed in 8 of the 17 patients). The karyotype groups had a significant impact on survival, the group with loss of a sex chromosome having a poorer outcome and the group with abnormalities of chromosome 9 having a better outcome. CD19 positivity was seen in 21 of the 33 cases (63%) in whom it was measured compared to 11% observed in controls with AML without a t(8;21). CD19 status did not exert any influence on event free survival. Extramedullary leukemia (EML) occurred in 5 of the 50 cases (10%). In one patient it was observed at diagnosis but in the others it presented concurrent with bone marrow relapse. The overall survival of patients with EML was worse than that of the other patients but did not achieve statistical significance and was probably adversely affected by other factors.

Acute Disease↗

PubMed1999

5,10,15,20-Tetrakis(4-N-methylpyridyl)porphyrinato-palladium(II ) as a differentiation probe for sensing binding modes with B-DNA duplexes: electronic MCD and CD spectra.

We report our detailed electronic MCD, CD, and optical spectroscopic measurements and analysis of the porphyrin Soret (B(o)) region of four-coordinate 5,10,15,20-tetrakis(4-N-methylpyridyl)porphyrinatopalladium( II), PdP(4), and its bound states with B-DNA duplexes poly(A-T)2, poly(G-C)2, and calf thymus DNA (CT DNA). For system PdP(4)/poly(A-T)2 it was possible to conclude that the porphyrin is bound edge-on in the major groove, specifically at the 5'AT3' site. For this orientation the porphyrin's electric dipole transition moments (edtm), mu(x) (most perturbed direction) and mu(y) (least perturbed direction), have tilt angles alpha approximately 90 degrees and approximately 45 degrees , respectively, relative to the helix axis. It was further concluded from the small shifts of B(o) optical and MCD band intensities and wavelengths and from the net MCD (+) A-term sign retention upon binding that the porphyrin's frontier ppi MOs (1a(1u) 3a(2u) 4eg) are only weakly perturbed by the heterocyclic bases of poly(A-T)2, and therefore that the LUMO (4eg) splitting is less than the |1a(1u)-3a(2u| energy separation, deltaHOMO, that is, deltaLUMO < deltaHOMO for the bound state in PdP(4)/poly(A-T)2. For intercalation systems PdP(4)/ poly(G-C)2 and /CT DNA, with PdP(4) centered in the intercalation "pocket" and having two of its 4-N-methylpyridyls extending into each of the major and minor grooves, the edtms mu(x) and mu(y) were determined to be oriented perpendicular (gamma approximately 0 degrees) and parallel (gamma approximately 90 degrees) to the hydrogen bonds of the base pairs, respectively. Intercalation is characterized by a much stronger binding interaction, viz., the B(o) optical band and net MCD extrema wavelength shifts are relatively large, and the net MCD (+) A-term of PdP(4) is substantially quenched as it becomes the (-) pseudo-A-term of intercalated PdP(4)/poly(G-C)2. This A-term sign reversal informs that the porphyrin MOs are so strongly perturbed by the GC base pairs that deltaLUMO > deltaHOMO, which gives rise to a (-) pseudo-A-term. Also, the findings demonstrate (1) the potential of PdP(4) as a sensitive, discriminating analytical probe of DNA sequences and (2) the diagnostic capability of the composite of five spectra [net MCD, CD, and optical of free and bound PdP(4)] in differentiating the site and sequence selectivity and preferred binding mode of this porphyrin.

Binding Sites↗

PubMed1999

Impact of previous high-dose therapy on outcome after allografting for multiple myeloma.

We describe a single centre experience of 33 patients allografted for multiple myeloma, of which 28 received matched sibling marrow, one haploidentical family donor marrow and four matched but unrelated donor marrow. Median follow-up after transplant is 27 months, and 13 patients are currently alive. One out of four patients with an unrelated donor survives and 12 out of 28 (42.8%) with matched sibling donors. Four patients were unevaluable because of early death (<day 21), and one patient experienced graft failure. The probability of overall survival is 35.7 % at 3 years. The probability of disease-free survival is 39% at 3 years, and the probability of treatment-related mortality is 54% at 1 year. Acute GVHD developed in 26 (78.8%) patients and was responsible for six deaths. Twenty-four patients (72.7%) developed renal dysfunction and 22 (66.7%) developed hepatic dysfunction. Seventeen patients (51.5%) died of transplant-related problems in the first 150 days, and one at 6 months. Among the 13 survivors, none has experienced disease progression at a median follow-up of 27 months (range 3-65 months). We conclude that since allogeneic bone marrow transplantation is the only potentially curative option in myeloma, it should be offered to younger patients early in the course of their disease, when procedure-related morbidity and mortality are likely to be at their lowest.

Adult↗

PubMed1999

Long-term outcome of adult acute leukemia patients who are alive and well 2 years after autologous blood or marrow transplantation.

We studied the long-term outcome of 87 adults with acute leukemia (age 15-59 years at transplant, median 27; 44 myeloid, 42 lymphoblastic, one biphenotypic) who were alive in continuous remission 2 years after a marrow (n = 74) or blood stem cell (n = 13) autograft. Nine relapsed 25-50 months (median 38) after transplantation. Five relapses were straightforward with no karyotypic or morphologic evolution of the original disease. Four recurrences were unusual, with development of myelodysplasia (n = 3) or myeloproliferative disease (n = 1). Five patients died of relapsed disease and four are still alive. Two patients died of complications related to the transplant, and one of ischemic heart disease. Seventy-nine patients (91%) are alive in remission 24-149 months (median 67) after transplantation (75 in continuous remission and four after further therapy) with Karnofsky scores of 80-100% (median 100%). The 8-year probabilities of survival, toxic death, and relapse (from the 2-year mark) are 89%, 3% and 12%. Eleven (12%) survivors had creatinine levels of >110 micromol/l (one more than double), and 14 (16%) had bilirubin levels of >17 mmol/l (one more than double) at the last follow-up. None of the following factors was found to be predictive for survival, non-relapse death, or relapse from the 2-year mark in multivariate analysis: age, sex, type of leukemia, disease stage, diagnosis, conditioning, origin of cells, and nucleated cell dose. We conclude that adult patients with acute leukemia who are alive and well 2 years following an autograft have a high probability of being cured, and the incidence of long-term liver and kidney dysfunction measured by serum bilirubin and creatinine is low.

Acute Disease↗