Ronald Brand

The choice of treatment of single brain metastasis should be based on extracranial tumor activity and age

PURPOSE To determine if in patients with single brain metastasis the addition of neurosurgery to radiotherapy leads to lengthening of survival or to better quality of life. METHODS AND MATERIALS From 1985 to 1990, 66 patients with single brain metastasis from a solid tumor were entered in a randomized trial of neurosurgery plus radiotherapy vs. radiotherapy alone. Patients were stratified for lung cancer vs. other sites of cancer and for progressive vs. stable systemic cancer. Radiotherapy was given to the whole brain by a novel scheme of two fractions of 2 Gy per day for a total dose of 40 Gy in 2 weeks, to obtain a relatively high total dose and short overall time, with minimal risk of late damage to normal tissue in long-term survivors. RESULTS In the whole group of 63 evaluable patients, both with lung cancer as with other tumors, the combined treatment led to a better duration of survival (median 10 vs. 6 months; p = 0.04). The largest difference between both treatment arms was observed in patients with inactive extracranial disease (median 12 vs. 7 months; p = 0.02). Patients with active extracranial disease had an equal median survival of only 5 months, irrespective of given treatment. Age proved to be a strong and independent prognostic factor: patients older than 60 years had a hazard ratio of dying of 2.74 (p = 0.003) compared with younger patients. Following treatment, most patients remained functionally independent until a few weeks before death. In the majority of patients the cause of death was systemic tumor progression. CONCLUSION Patients with single brain metastasis and with controlled or absent extracranial tumor activity should be treated with surgery and radiotherapy, especially when they are younger than 60 years. For patients with progressive extracranial disease, radiotherapy alone seems to be sufficient. The accelerated radiotherapy scheme of 40 Gy in 2 weeks to the whole brain is tolerated well and should also be considered for patients in a good performance status with surgically unaccessible single metastasis or even with multiple brain metastases.

Total Ankle Arthroplasty in Inflammatory Joint Disease with Use of Two Mobile-Bearing Designs

BACKGROUND Interest in mobile-bearing total ankle arthroplasty has increased in recent years. However, to our knowledge, no study has focused exclusively on patients with the diagnosis of inflammatory joint disease or has provided a detailed analysis of the risk factors for failure. METHODS A prospective observational study of the results of cementless mobile-bearing total ankle arthroplasty in patients with inflammatory joint disease (mainly rheumatoid arthritis) was conducted at two centers. Ninety-three total ankle arthroplasties were performed. The LCS (low contact stress) prosthesis was used initially, in nineteen ankles, between 1988 and 1992, and a modification of the LCS prosthesis, the Buechel-Pappas design, was used in seventy-four ankles between 1993 and 1999. Clinical and radiographic follow-up was performed at yearly intervals. Three clinical scoring systems were used, and any complication was recorded throughout follow-up. Actuarial survival (with revision as the end point), multivariate analysis, and a competing risk approach were used to describe the long-term outcome. RESULTS The clinical result at one year after surgery showed a significant improvement in the scores on all three scoring systems (p < 0.05). Ankle dorsiflexion (mean, 7 degrees ) also improved significantly (p < 0.05) compared with the preoperative state. The most frequent complication was a malleolar fracture, which occurred in twenty ankles. Only when it occurred in combination with a deformity in the frontal plane did this complication have an adverse effect on the end result. At a mean follow-up of eight years, seventeen patients (twenty-one ankles) had died and fifteen ankles had been revised because of aseptic loosening (six ankles), primary or secondary axial deformity with edge-loading (six ankles), deep infection (two ankles), and a severe wound-healing problem (one ankle), leaving fifty-seven ankles (61%) that were evaluated. The mean overall survival rate at eight years was 84%. An increased failure rate was encountered in ankles with a preoperative deformity in the frontal plane of >10 degrees (p = 0.03) and in ankles in which an undersized tibial component had been implanted (p = 0.02). CONCLUSIONS Mobile-bearing total ankle arthroplasty is a valid treatment option for the rheumatoid ankle if proper indications are used. Aseptic loosening and persistent deformity are the most important modes of failure.

Risk Score for Outcome After Allogeneic Hematopoietic Stem Cell Transplantation: A Retrospective Analysis

It was investigated whether the European Group for Blood and Marrow Transplantation risk score, previously established for chronic myeloid leukemia, could be used to predict outcome after allogeneic hematopoietic stem cell transplantation (HSCT) for hematological disease in general.

Allogeneic stem cell transplantation after reduced-intensity conditioning in patients with myelofibrosis: a prospective, multicenter study of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation.

From 2002 to 2007, 103 patients with primary myelofibrosis or postessential thrombocythemia and polycythemia vera myelofibrosis and a median age of 55 years (range, 32-68 years) were included in a prospective multicenter phase 2 trial to determine efficacy of a busulfan (10 mg/kg)/fludarabine (180 mg/m(2))-based reduced-intensity conditioning regimen followed by allogeneic stem cell transplantation from related (n = 33) or unrelated donors (n = 70). All but 2 patients (2%) showed leukocyte and platelet engraftment after a median of 18 and 22 days, respectively. Acute graft-versus-host disease grade 2 to 4 occurred in 27% and chronic graft-versus-host disease in 43% of the patients. Cumulative incidence of nonrelapse mortality at 1 year was 16% (95% confidence interval, 9%-23%) and significantly lower for patients with a completely matched donor (12% vs 38%; P = .003). The cumulative incidence of relapse at 3 years was 22% (95% confidence interval, 13%-31%) and was influenced by Lille risk profile (low, 14%; intermediate, 22%; and high, 34%; P = .02). The estimated 5-year event-free and overall survival was 51% and 67%, respectively. In a multivariate analysis, age older than 55 years (hazard ratio = 2.70; P = .02) and human leukocyte antigen-mismatched donor (hazard ratio = 3.04; P = .006) remained significant factors for survival. The study was registered at www.clinicaltrials.gov as #NCT 00599547.

Outcome of very preterm small for gestational age infants: the first nine years of life

Objective To determine the influence of intrauterine growth retardation of preterm infants on mortality and cognitive development.

Treatment of acquired severe aplastic anemia: Bone marrow transplantation compared with immunosuppressive therapy-the European group for blood and marrow transplantation experience☆

Patients with severe aplastic anemia (SAA) can be successfully treated with bone marrow transplantation (BMT) or immunosuppressive therapy (IS). The current outcome using both forms of therapy among 3,669 patients treated in Europe between 1976 and 1998 is reviewed. Significant progress has been made and the overall risk of failure is now low, with survival rates greater than 80% for both treatments. Chronic graft-versus-host disease (GvHD) remains a problem for BMT patients, and carries a high risk of lethal complications. On the other hand, IS patients are exposed to late failure due to relapse or clonal/malignant diseases. First-line BMT from identical siblings is compared with IS therapy in an intent-to-treat analysis of 1,765 patients, regardless of subsequent transplant status. The outcome of SAA patients has improved considerably over time and is influenced by patient variables such as severity of the disease and age, but also by the choice of the initial treatment.

The relation between neonatal thyroxine levels and neurodevelopmental outcome at age 5 and 9 years in a national cohort of very preterm and/or very low birth weight infants

Transient neonatal hypothyroxinemia is very common in preterm infants. The literature on the effect of this hypothyroxinemia is, however, controversial, and large or long-term follow-up studies are not available. In a nationwide prospective follow-up study on very preterm and (or) very low birth weight infants (n = 717), we studied the relationship between thyroxine levels in the 1st wk of life and neurodevelopmental outcome at 5 y of age and school performance at 9 y of age. Thyroxine concentrations from filter paper eluates were determined in 717 infants: 32% had levels of more than 3 SD below the mean (<60 nmol/L). The percentage of infants with such low levels increased with decreasing gestational age. At the age of 5 y, 96% of survivors(n = 640) were available for extensive neurodevelopmental examination: 85 (13.3%) had a disability and 92 (14.3%) a handicap. At the age of 9 y, 83% of survivors (n = 552) answered a questionnaire on school performance: 300 (54.3%) were in mainstream education in a grade appropriate for age, 151 (27%) were in mainstream education with grade retention, and 101 (18.3%) were in special education. Both neurologic dysfunction at age 5 y and school failure at age 9 y were significantly related to lower neonatal thyroxine levels even after adjustment for other perinatal factors (odds ratio, 1.3). Whether this relationship is causal should be investigated. If a causal relationship exists, substitution therapy may at least partially prevent neurologic dysfunction and learning disabilities, both common sequelae of very preterm birth.

School performance at nine years of age in very premature and very low birth weight infants: Perinatal risk factors and predictors at five years of age

To assess the impact of both perinatal disorders and developmental problems identified at preschool age on school performance, we followed a virtually complete birth cohort of very premature (< 32 completed weeks of gestation) and very low birth weight infants until they were 9 years of age. In 84% of the survivors (n = 813), data on school performance were available for analysis. At the age of 9 years, 19% of the children were in special education. Of the children in mainstream education, 32% were in a grade below the appropriate level for age and 38% had special assistance. After correction for other perinatal items, children of low socioeconomic status and boys had significantly higher adjusted odds ratios for special education. Logistic regression with a perinatal and a 5-year time category showed that the most predictive factors for special education were developmental delay, neuromotor and speech/language function, inattention and hyperactivity score, total problem score, and reported school results at the age of 5 years. When children with disabilities were left out of the analysis, the importance of neuromotor function and total problem score disappeared. Increased risks of any school failure in nondisabled children included mild or severe developmental delay and marginal or poor school performance at the age of 5 years. Long-term follow-up with specific attention to these predictors at 5 years of age, although time-consuming, is necessary.

Allogeneic Hematopoietic Stem-Cell Transplantation for Patients 50 Years or Older With Myelodysplastic Syndromes or Secondary Acute Myeloid Leukemia

PURPOSE This study was performed to examine the characteristics of transplant activity for patients with myelodysplastic syndromes (MDS) older than 50 years within the European Group for Blood and Marrow Transplantation, and to evaluate the factors predicting outcome within this group of patients. PATIENTS AND METHODS We performed a retrospective multicenter analysis of 1,333 MDS patients age 50 years or older who received transplantation within the EBMT since 1998. The median recipient age was 56 years, with 884 patients (66%) age 50 to 60 years and 449 (34%) patients older than 60 years. There were 811 HLA-matched sibling (61%) and 522 (39%) unrelated donor transplants. Five hundred patients (38%) received standard myeloablative conditioning (SMC), and 833 (62%) received reduced intensity conditioning (RIC). RESULTS The 4-year estimate for overall survival of the whole cohort was 31%. On multivariate analysis, use of RIC (hazard ratio [HR], 1.44; 95% CI, 1.13 to 1.84; P < .01) and advanced disease stage at transplantation (HR, 1.51; 95% CI, 1.18 to 1.93; P < .01) were associated with an increased relapse rate. In contrast, advanced disease stage at transplantation (HR, 1.43; 95% CI, 1.13 to 1.79; P = .01), use of an unrelated donor (P = .03), and RIC (HR, 0.79; 95% CI, 0.65 to 0.97; P = .03) were independent variables associated with nonrelapse mortality. Advanced disease stage at transplantation (HR, 1.55; 95% CI, 1.32 to 1.83; P < .01) was the major independent variable associated with an inferior 4-year overall survival. CONCLUSION Allogeneic hematopoietic stem-cell transplantation remains a potential curative therapeutic option for many older patients with MDS. In this analysis, disease stage at time of transplantation, but not recipient age or the intensity of the conditioning regimens, was the most important factor influencing outcomes.

Double-Blind, Randomized Controlled Trial on the Effect of Leukocyte-Depleted Erythrocyte Transfusions in Cardiac Valve Surgery

Background—Leukocytes in allogeneic blood transfusions are believed to be the cause of immunomodulatory events. A few trials on leukocyte removal from transfusions in cardiac surgery have been conducted, and they showed inconclusive results. We found in a previous study a decrease in mortality rates and number of infections in a subgroup of more heavily transfused patients. Methods and Results—Patients (n= 496) undergoing valve surgery (with or without CABG) were randomly assigned in a double-blind fashion to receive standard buffy coat–depleted (PC) or prestorage, by filtration, leukocyte-depleted erythrocytes (LD). The primary end point was mortality at 90 days, and secondary end points were in-hospital mortality, multiple organ dysfunction syndrome, infections, intensive care unit stay, and hospital stay. The difference in mortality at 90 days was not significant (PC 12.7% versus LD 8.4%; odds ratio [OR], 1.52; 95% confidence interval [CI], 0.84 to 2.73). The in-hospital mortality rate was almost twice as high in the PC group (10.1% versus 5.5% in the LD group; OR, 1.99; 95% CI, 0.99 to 4.00). The incidence of multiple organ dysfunction syndrome in both groups was similar, although more patients with multiple organ dysfunction syndrome died in the PC group. LD was associated with a significantly reduced infection rate (PC 31.6% versus LD 21.6%; OR, 1.64; 95% CI, 1.08 to 2.49). In both groups, intensive care unit stay and hospital stay were similar, and postoperative complications increased with the number of transfused units. Conclusions—Mortality at 90 days was not significantly different; however, a beneficial effect of LD in valve surgery was found for the secondary end points of in-hospital mortality and infections.