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Biomedical subjects

D W Milligan

Publications and source records attributed to D W Milligan.

At least 37 records · Page 2Linked to original sources

Pulse oximetry, severe retinopathy, and outcome at one year in babies of less than 28 weeks gestation.

AIM: To determine whether differing policies with regard to the control of oxygen saturation have any impact on the number of babies who develop retinopathy of prematurity and the number surviving with or without signs of cerebral palsy at one year. METHODS: An examination of the case notes of all the 295 babies who survived infancy after delivery before 28 weeks gestation in the north of England in 1990-1994. RESULTS: Babies given enough supplemental oxygen to maintain an oxygen saturation of 88-98%, as measured by pulse oximetry, for at least the first 8 weeks of life developed retinopathy of prematurity severe enough to be treated with cryotherapy four times as often as babies only given enough oxygen to maintain an oxygen saturation of 70-90% (27.2% v 6.2%). Surviving babies were also ventilated longer (31.4 v 13.9 days), more likely to be in oxygen at a postmenstrual age of 36 weeks (46% v 18 %), and more likely to have a weight below the third centile at discharge (45% v 17%). There was no difference in the proportion who survived infancy (53% v 52%) or who later developed cerebral palsy (17% v 15%). The lowest incidence of retinopathy in the study was associated with a policy that made little use of arterial lines. CONCLUSIONS: Attempts to keep oxygen saturation at a normal "physiological" level may do more harm than good in babies of less than 28 weeks gestation.

Clinical Protocols↗

Foot length, an accurate predictor of nasotracheal tube length in neonates.

BACKGROUND: Existing guidelines for optimal positioning of endotracheal tubes in neonates are based on scanty data and relate to measurements that are either non-linear or poorly reproducible in sick infants. Foot length can be measured simply and rapidly and is related to a number of external body measurements. OBJECTIVES: To evaluate the relation of foot length to nasotracheal length in direct measurements at post mortem examinations, and then compare its clinical relevance with traditional weight based estimates in a randomised controlled trial. METHODS: The dimensions of the upper airway were measured at autopsy in 39 infants with median (range) postmenstrual age and birth weight of 32 (24-43) weeks and 1630 (640-3530) g. The regression equations with 95% prediction intervals were calculated to estimate the optimal nasotracheal length from foot length. In a randomised trial, 59 neonates were nasally intubated according to foot length and body weight based estimates to assess the achievement of "optimal" and "satisfactory" tube placements. RESULTS: In the direct measurements of the airway at autopsy, foot length was a better predictor of nasotracheal distances (r(2) = 0.79) than body weight, gestational age, and head circumference (r(2) = 0.67, 0.58, and 0.60 respectively). Measurement of foot length was easy and highly reproducible. In the randomised controlled trial, there were no significant differences between the foot length and body weight based estimates in the rates of optimal (44% v 56%) and satisfactory (83% v 72%) endotracheal tube placements. CONCLUSIONS: Foot length is a reliable and reproducible predictor of nasotracheal tube length and is at least as accurate as the conventional weight based estimation. This method may be particularly valuable in sick unstable infants.

Analysis of Variance↗

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↗

Resistance to antiviral drugs in herpes simplex virus infections among allogeneic stem cell transplant recipients: risk factors and prognostic significance.

Herpes simplex virus (HSV) infections in 75 allogeneic stem cell transplant recipients were analyzed. Sixteen patients developed HSV disease following transplantation. The risk factors were age, sex (females), unrelated donor graft, and graft-versus-host disease (GVHD) grade >/=2. Seven patients did not respond to acyclovir, and 3 patients failed to respond to foscarnet. Isolates from 4 patients developed resistance to acyclovir/penciclovir, and 3 patients had foscarnet-resistant isolates. The remaining 3 patients failed to respond to acyclovir, despite having sensitive isolates. All the isolates were sensitive to cidofovir, for which the IC(50) values correlated inversely with those for acyclovir (P=.01). The risk factors for clinical resistance to antiviral drugs were a GVHD grade >/=2 (P=.001) and the lack of ganciclovir prophylaxis (P=.01), with a higher nonrelapse mortality in the latter group (P<.0001). Clinical as well as in vitro resistance to antiviral drugs is common in patients with severe GVHD and is associated with a poor outcome.

Acyclovir↗

Pumactant and poractant alfa for treatment of respiratory distress syndrome in neonates born at 25-29 weeks' gestation: a randomised trial.

BACKGROUND: Exogenous surfactant preparations vary in their constitution and biophysical properties. Synthetic and animal-derived preparations lower the rate of death compared with controls. No significant differences in mortality or important long-term clinical outcomes have been shown between them in randomised trials. We did a randomised controlled trial to compare pumactant, a synthetic surfactant, with poractant alfa, an animal-derived surfactant, both of which are widely used in the UK. METHODS: We enrolled 212 neonates born between 25 weeks' and 29 weeks and 6 days' gestation who were intubated for presumed surfactant deficiency and were free from life-threatening malformations. We randomly assigned 105 neonates poractant alfa, and 107 pumactant. The primary outcome was duration of high-dependency care and mortality was a secondary outcome. Analysis was by intention to treat. FINDINGS: Outcome data were analysed for 199 babies. The trial was stopped on the recommendation of the data and safety monitoring committee because mortality assumed a greater importance than the primary outcome. Predischarge mortality differed significantly between groups, in favour of poractant alfa (14.1 vs 31.0%, p=0.006; odds ratio 0.37 [95% CI 0.18-0.76). This difference was sustained after adjustment for centre, gestation, birthweight, sex, plurality, and use of antenatal steroids. INTERPRETATION: Mortality was unexpectedly lower among neonates who received poractant alfa than among those who received pumactant, and was independent of all the variables we investigated. Stopping the trial early may have widened the difference between the treatment groups.

Cause of Death↗

Isolation of viruses from stools in stem cell transplant recipients: a prospective surveillance study.

We prospectively examined stool specimens for enteric viruses in 75 stem cell transplant recipients (autologous 48, allogeneic 27) to determine the frequency and significance of these infections. Only six patients (8%) had a positive isolate. Five of these were allograft recipients (18%) compared to one autograft recipient (2%) (P = 0.02). Unrelated donor BMT recipients were at the highest risk for a viral isolate (OR = 10.5). Adenovirus was the commonest isolate (four patients). One patient each had an echovirus, enterovirus and small round structured virus identified. No correlation was found between the severity of gastro-intestinal symptoms and detection of a viral pathogen. There was no correlation with GVHD or CMV status. The only risk factor identified for isolation of an enterovirus was allogeneic BMT from an unrelated donor. There was a negative correlation with PBSC grafts. All the patients infected with an enteric virus had concomitant infection with other pathogens, compared to only 18% of uninfected patients (P = 0.001). The non-relapse mortality of the infected patients was 50% and only 7% in the uninfected patients (P = 0.01, OR = 12.5), although the isolated virus was the direct cause of death in one patient only. This study indicates a low rate of enteric virus isolation in recipients of PBSC grafts, both autologous and allogeneic. However, unrelated donor BMT is associated with a higher risk of enteric virus infection and an adverse outcome. Bone Marrow Transplantation (2000) 25, 277-282.

Adenoviridae↗

Adenovirus infections following haematopoietic cell transplantation: is there a role for adoptive immunotherapy?

Adenovirus has been recognised as an important pathogen in BMT recipients, especially in patients with GVHD and those receiving T cell-depleted allografts. We report adenovirus infections from an ongoing surveillance study in four patients after a non-myeloablative transplant and their improved outcome following withdrawal of immunosuppression in two patients and donor lymphocyte infusion for relapsed disease in the others. We discuss the control of adenovirus infections following immune manipulations and the feasibility of adoptive immunotherapy for post-transplant adenovirus infections.

Adenoviridae Infections↗

Clostridium difficile infection in allogeneic stem cell transplant recipients is associated with severe graft-versus-host disease and non-relapse mortality.

We retrospectively evaluated 75 allogeneic stem cell transplant recipients to ascertain the incidence, risk factors and outcome of infection with Clostridium difficile. Ten patients (13%) had Clostridium difficile infection at a median of 38 days (range day -6 to day +72) following the transplant. There was no difference in the duration or severity of diarrhoea in patients with Clostridium difficile infection compared to the uninfected patients and no relationship to the prior antibiotic or chemotherapy usage, age, gender, underlying disease, donor type, CMV serostatus, total body irradiation or time to engraftment. The incidence of viral infections was increased in patients infected with Clostridium difficile (7/10 vs 15/65, P = 0.005, odds ratio 7.7), but the strongest association was with GVHD >grade 2 (5/10 vs 6/65 uninfected patients, P = 0.004, odds ratio 9.8). Patients infected with Clostridium difficile also suffered a higher non-relapse mortality with 7/10 patients succumbing to either GVHD or infections, compared to 19/65 patients in the uninfected group (P = 0.02, odds ratio 5.6). Thus Clostridium difficile infections in our study had a strong association with GVHD and increased non-relapse mortality. It is possible that Clostridium difficile toxin might predispose to increased severity of GVHD leading to an adverse outcome.

Adolescent↗

Philadelphia-positive T-ALL in a patient with follicular lymphoma.

Follicular lymphoma is a B cell malignancy prone to transformation into a large cell diffuse histology. This progression may be multi-clonal as determined by IgH rearrangement. Similar multi-clonal occurrences have been described in immunocompromised patients. However, the lymphoma cells remain predominantly of B cell type. Rarely, composite lymphomas with diffuse T cell histology have been reported arising from follicular lymphoma. The development of T cell leukaemia in a patient with a pre-existing B cell malignancy is an extremely rare event. The occurrence of T cell acute lymphoblastic leukaemia (T-ALL) following follicular lymphoma (FL) has not previously been reported. We report a case of Philadelphia positive (Ph+) T cell ALL developing in a patient who previously had FL which may give some insight into the cell of origin and the defects responsible for malignant transformation of the lymphocytes.

Adult↗

An analysis of the effect of chronic GvHD on relapse and survival following allogeneic PBSC transplantation.

BACKGROUND: PBSC are increasingly being used as the source of stem cells in allogeneic transplantation. An increased incidence of chronic GvHD has been suggested following unmanipulated allogeneic PBSC transplantation (PBSCT), however, how this affects overall survival is not yet clear. Our aim was to study the impact of chronic GvHD on survival and relapse following allogeneic PBSCT. METHODS: We have analyzed data from 73 patients undergoing HLA-matched allogeneic PBSCT. GvHD prophylaxis was with CYA and MTX in 97% of patients. We have studied the incidence of chronic GvHD and its affect on relapse and survival in these patients. All patients were at least 100 days post-transplant at the time of analysis. RESULTS: Seventy-three patients were evaluable for analysis of chronic GvHD. The overall incidence of chronic GvHD was 55% (limited in 18% and extensive in 37%). Overall median survival was 991 days, with a 4 year survival rate of 48%. Twelve patients relapsed. Patients with chronic GvHD had a significantly lower incidence of disease relapse (p = 0.005) with a relapse probability of 8% at 3 years, compared with 40% in patients with no chronic GvHD. In addition, the extent of chronic GvHD had a marked effect on survival, patients with limited chronic GvHD had a 4 year survival rate of 83%, compared with 45% in patients with extensive chronic GvHD and 38% in patients with no chronic GvHD. This difference was primarily due to the low incidence of relapse and low mortality seen in patients with limited chronic GvHD. DISCUSSION: The presence and extent of chronic GvHD is an important predictor of outcome following allogeneic PBSCT, in that patients who developed either limited or extensive chronic GvHD had a low risk of disease relapse.

Adolescent↗

Secondary leukaemia and myelodysplasia after autografting for lymphoma: is the transplant to blame?

Haemopoietic stem cell autografting is becoming a standard part of the therapeutic repertoire for salvage of relapsed lymphoma patients. Over the last five years or so a number of studies have identified that such patients are at high risk of developing secondary acute myeloid leukaemia (AML) or myelodysplastic syndromes (MDS). The actuarial risks have been estimated to be up to 18% in some series. More recently, studies from France and the EBMT suggest that in Registries containing large numbers of transplanted patients the risks are lower and are of the order of 3-5% at five years. Cytogenetic examination of bone marrow cells taken pre-transplant may also show identical abnormalities to those found in the leukaemic clone after transplant indicating that in many instances the stem cell damage was caused by prior treatment. In addition, a report from the British National Lymphoma Investigation has identified that post-transplant MDS/AML was related to the total quantity of treatment received, with mustine being identified as a particular culprit. It thus seems probable that the additional stem cell insult offered by the transplant may be small although a factor which may increase the risk is the use of total body irradiation.

Hematopoietic Stem Cell Transplantation↗

Fulminant adenovirus hepatitis following unrelated bone marrow transplantation: failure of intravenous ribavirin therapy.

Fulminant hepatic failure due to adenovirus infection is a rare complication following stem cell transplantation. We report this complication in an unrelated bone marrow transplant recipient 30 weeks post-transplant. Treatment with intravenous ribavirin was started within 36 h of admission, but he succumbed to unusually fulminant hepatic failure. Adenovirus type 2 was isolated from stool surveillance samples and from post-mortem liver samples. Adenovirus DNA was detected by PCR in blood and sputum samples at admission and was identified in post-mortem liver tissue by electron microscopy. Implications of the failure of ribavirin therapy are discussed.

Adenoviridae Infections↗

Syngeneic transplantation in multiple myeloma - a case-matched comparison with autologous and allogeneic transplantation. European Group for Blood and Marrow Transplantation.

Twenty-five patients with multiple myeloma received bone marrow grafts (n = 24) or peripheral blood stem cells (n = 1) from twin donors. The outcome was compared in a case-matched analysis to 125 patients who underwent autologous transplantation, and 125 who underwent allogeneic transplantation. Seventeen patients (68%) receiving twin transplants entered complete remission, which was not significantly different from that of autologous (48%) or allogeneic (58%) transplants. The median overall and progression-free survival for the twins was 73 and 72 months, respectively. The overall survival tended to be better (73 vs 44 months) and the progression-free survival was significantly better (72 vs 25 months) than with autologous transplantation and both were significantly better than with allogeneic transplantation. Three of 17 patients who entered complete remission following transplantation had relapsed at follow-up. This relapse rate was significantly lower than following autologous transplantation and similar to the relapse rate with allogeneic transplantation. Only two twins died of transplant-related toxicity. Six further patients died of progressive or relapsing disease. Syngeneic transplantation in multiple myeloma appears to be the treatment of choice if a twin donor is available. A lower relapse risk than in autotransplantation may be due to reinfusion of malignant cells in some patients treated with this modality or to the presence of a graft-versus-myeloma effect in some syngeneic transplants.

Adult↗

The sequential analysis of trisomy 12 in B-cell chronic lymphocytic leukaemia.

In this longitudinal study we evaluated the clinical significance of screening for trisomy 12 by fluorescence in situ hybridization (FISH) and correlated these findings with survival, disease progression and need for treatment. Interphase FISH was performed on 85 patients in 1993/94 and repeated on 41 patients in 1996/97. Over the 4-year period there was no significant change in the percentage of trisomic cells, even in patients with disease progression. Overall survival and requirement for treatment were similar for patients with and without FISH-defined trisomy 12.

Chromosomes, Human, Pair 12↗

Phase III efficacy study of interleukin-3 after autologous bone marrow transplantation in patients with malignant lymphoma.

We evaluated the efficacy of recombinant human interleukin-3 (rhIL-3) in reducing the number of platelet transfusions and major infections after autologous bone marrow transplantation (ABMT) in patients with malignant lymphoma. 198 patients with non-Hodgkin's lymphoma (NHL, n = 111) and Hodgkin's disease (HD, n = 87) were randomized to receive rhIL-3 10 microgram/kg/d (n = 130) or placebo (n = 68) for a maximum of 28 d after ABMT. Several well-known conditioning regimens were used. From day 1 after ABMT patients were treated with placebo or rhIL-3 at a dose of 10 microgram/kg/d by continuous i.v. infusion for 7 d and then by s.c. administration for 21 d or until platelet (50 x 109/l) and neutrophil (0.5 x 109/l) recovery had occurred. Treatment was completed in 54% of the patients in the rhIL-3 group versus 75% in the placebo group (P < 0.004). Adverse events were the main reason for premature discontinuation in the IL-3 group (23% IL-3 v 5% placebo). The median number of platelet transfusions was not significantly different between the IL-3 group and the placebo group (8.0 IL-3 v 6.0 placebo, P = 0.09). Platelet engraftment (>/= 20 x 109/l) was not significantly faster in the IL-3 group (28 d in the IL-3 and 27 d in the placebo group, P = 0.06) and the incidence of haemorrhagic complications was similar in both groups. In patients receiving the full intended dose of rhIL-3, platelet engraftment to >/= 20 x 109/l was delayed (P = 0.007). The median time to neutrophil engraftment was 23 d in the IL-3 and 25 d for the placebo group (P = 0.39). There was no difference in the incidence of major infections. We conclude that treatment with IL-3 has no clinical benefit in patients receiving ABMT for malignant lymphoma.

Bone Marrow Transplantation↗

Secondary leukaemia and myelodysplasia after autografting for lymphoma: results from the EBMT. EBMT Lymphoma and Late Effects Working Parties. European Group for Blood and Marrow Transplantation.

Between 1978 and 1996 more than 7500 lymphoma transplants have been reported to the European Bone Marrow Transplantation (EBMT) Lymphoma Registry. This has been examined to establish the incidence of secondary leukaemia and myelodysplasia and to relate this to possible prognostic factors. 131 centres representing 4998 patients responded to a questionnaire. This identified 66 patients with post transplant myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML). The actuarial risk for MDS/AML at 5 years post-transplant (+/-95% CI) was 4.6% (3.1-6.8) for Hodgkin's disease and 3.0% (2.0-4. 3) for non-Hodgkin's lymphoma. Multivariate analysis for all patients demonstrated an effect of age at transplant, radiotherapy at conditioning, number of transplants and interval between diagnosis and transplant as risk factors. For patients with NHL, grade of histology was important (low grade > intermediate or high-grade); for Hodgkin's disease, female sex was identified as a risk factor. These findings suggest that the incidence of MDS/AML may not be greater following an autograft than after conventional chemotherapy.

Adolescent↗