Clinical impact of minimal residual disease in children with different subtypes of acute lymphoblastic leukemia treated with Response-Adapted therapy.

To determine the clinical significance of minimal residual disease (MRD) in patients with prognostically relevant subtypes of childhood acute lymphoblastic leukemia (ALL), we analyzed data from 488 patients treated in St Jude Total Therapy Study XV with treatment intensity based mainly on MRD levels measured during remission induction. MRD levels on day 19 predicted treatment outcome for patients with hyperdiploid >50 ALL, National Cancer Institute (NCI) standard-risk B-ALL or T-cell ALL, while MRD levels on day 46 were prognostic for patients with NCI standard-risk or high-risk B-ALL. Patients with t(12;21)/(ETV6-RUNX1) or hyperdiploidy >50 ALL had the best prognosis; those with a negative MRD on day 19 had a particularly low risk of relapse: 1.9% and 3.8%, respectively. Patients with NCI high-risk B-ALL or T-cell ALL had an inferior outcome; even with undetectable MRD on day 46, cumulative risk of relapse was 12.7% and 15.5%, respectively. Among patients with NCI standard-risk B-ALL, the outcome was intermediate overall but was poor if MRD was ⩾1% on day 19 or MRD was detectable at any level on day 46. Our results indicate that the clinical impact of MRD on treatment outcome in childhood ALL varies considerably according to leukemia subtype and time of measurement.

A revised definition for cure of childhood acute lymphoblastic leukemia.

With improved contemporary therapy, we reassess long-term outcome in patients completing treatment for childhood acute lymphoblastic leukemia (ALL) to determine when cure can be declared with a high degree of confidence. In six successive clinical trials between 1984 and 2007, 1291 (84.5%) patients completed all therapies in continuous complete remission. The post-therapy cumulative risk of relapse or development of a second neoplasm and the event-free survival rate and overall survival were analyzed according to the presenting features and the three treatment periods defined by relative outcome. Over the three treatment periods, there has been progressive increase in the rate of event-free survival (65.2% vs 74.8% vs 85.1% (P<0.001)) and overall survival (76.5% vs 81.1% vs 91.7% (P<0.001)) at 10 years. The most important predictor of outcome after completion of therapy was the type of treatment. In the most recent treatment period, which omitted the use of prophylactic cranial irradiation, the post-treatment cumulative risk of relapse was 6.4%, death in remission 1.5% and development of a second neoplasm 2.3% at 10 years, with all relapses except one occurring within 4 years of therapy. None of the 106 patients with the t(9;22)/BCR-ABL1, t(1;19)/TCF3-PBX1 or t(4;11)/MLL-AFF1 had relapsed after 2 years from completion of therapy. These findings demonstrate that with contemporary effective therapy that excludes cranial irradiation, approximately 6% of children with ALL may relapse after completion of treatment, and those who remain in remission at 4 years post treatment may be considered cured (that is, less than 1% chance of relapse).

Regularized multiframe phase-shifting algorithm for three-dimensional profilometry.

In many industrial inspection systems, it is required to have a high-precision three-dimensional measurement of an object under test. A popular technique is phase-measuring profilometry. In this paper, we develop some phase-shifting algorithms (PSAs). We propose a novel smoothness constraint in a regularization framework; we call this the R-PSA method and show how to obtain the desired phase measure with an iterative procedure. Both the simulation and experimental results verify the efficacy of our algorithm compared with current multiframe PSAs for interferometric measurements.

Osteonecrosis in children after allogeneic hematopoietic cell transplantation: study of prevalence, risk factors and longitudinal changes using MR imaging.

Osteonecrosis after hematopoietic SCT (HCT) has seldom been addressed in pediatric populations. At our institution, since January 2002, children undergoing allogeneic HCT (alloHCT) receive yearly follow-up magnetic resonance imaging (MR) of hips and knees. To estimate the prevalence, longitudinal changes and associated risk factors for osteonecrosis after alloHCT, we reviewed MRs for children who underwent single alloHCT during the study period. We analyzed 149 of 344 patients who had post-HCT MR imaging performed (84 males; median age 11 years (range, 0.5-21 years)), median follow-up time was 32.6 months (range, 2.8-97.2 months). In all, 44 (29.5%) developed osteonecrosis of hips and/or knees; of those, 20 (45%) had at least 30% epiphyseal involvement. In 23 (52%), osteonecrosis lesions were identified in the first and in 43 (98%) by the third yearly scan. Knees were more frequently involved than hips; severity of osteonecrosis was greater in hips. Those who had pre-alloHCT osteonecrosis, two patients' hips and six patients' knees resolved completely; three patients' osteonecrosis lesions regressed after alloHCT. On risk factor analysis, age at time of alloHCT (P=0.051) and osteonecrosis identified by MRs before alloHCT (P=0.001) were the primary risk factors. This analysis shows that preventive strategies for osteonecrosis in this population should focus on measures to minimize risk factors before alloHCT.

Prevalence of osteonecrosis and associated risk factors in children before allogeneic BMT.

Osteonecrosis (ON) is a debilitating long-term complication of allogeneic BMT (allo-BMT), but may begin before allo-BMT in some children because of their primary disease treatment. Therefore, to estimate the prevalence and associated risk factors for ON before allo-BMT, we conducted a retrospective analysis of magnetic resonance (MR) studies of 118 children who underwent first allo-BMT at our institution between December 2000 and September 2007. Of the 118 consecutive patients, 107 (90.7%) underwent prospective MR studies irrespective of symptoms (69 males; median age at allo-BMT 12.9 years), and 11 underwent MR studies for symptoms. Among the 107 who had prospective imaging, 23 (21.5%) had ON; nearly 50% had at least 30% epiphyseal involvement. Knees were more frequently involved than were hips; severity of ON was greater in hips. ON prevalence before allo-BMT was 23.72% when all 118 patients were included in the denominator. Risk factor analysis, limited to MR studies performed irrespective of symptoms, revealed female gender (P=0.049) and age 10 years at the time of MR study (P=0.03) as significant risk factors, and primary diagnosis of lymphoid malignancies and aplastic anemia trended toward significance. ON before allo-BMT is a common occurrence in children.

Genetic polymorphisms of Chinese patients with ischemic stroke and concurrent stenoses of extracranial and intracranial vessels.

The etiology of concurrent stenoses of extracranial and intracranial vessels in patients with ischemic stroke is poorly understood, but hereditary factors are believed to be important. We aimed to determine whether genetic polymorphisms affecting homocysteine and lipid metabolism are associated with concurrent stenoses. The genotypes of 191 Han Chinese patients with acute ischemic stroke, of whom 47 (25%) had concurrent stenoses, and 167 healthy control patients in Hong Kong were examined for the following polymorphisms: paraoxonase 1 (PON1) Q192R, methylenetetrahydrofolate reductase (MTHFR) A222V, glutamate-cysteine ligase catalytic-subunit (GCLC)-129C>T, and oxidized low-density lipoprotein receptor (OLR) 3' untranslated region C>T (rs1050283). The genotype distributions of PON1 Q192R and MTHFR A222V, which affect lipid and homocysteine metabolism, differed significantly between patients with stroke and healthy controls. The presence of at least one R allele in PON1 Q192R and a TT allele in OLR rs1050283 were associated with concurrent stenoses. We also identified a possible association between the presence of at least one V allele in MTHFR A222V and concurrent stenoses. This study shows that genetic polymorphisms affecting homocysteine and lipid metabolism are possible risk factors for stroke and concurrent stenoses.

Use of magnetic resonance angiography to predict long-term outcomes of ischemic stroke patients with concurrent stenoses in Hong Kong.

PURPOSE: To determine the long-term outcome of ischemic stroke patients with concurrent intracranial and extracranial atherosclerosis using magnetic resonance angiography. METHODS: A prospective cohort of patients in Hong Kong with acute ischemic stroke was studied with magnetic resonance angiography of the brain and carotid duplex. All patients were followed up regularly for the development of recurrent stroke, cardiac events, or death. RESULTS: Totally 343 patients with acute ischemic stroke were included, of whom 104 (30%) had concurrent intracranial and extracranial lesions. The follow-up period was up to 76 months (mean 44.5 months). Overall, 55 patients (15.5%) died of any cause and 91 patients (26.5%) suffered a further nonfatal vascular event. The overall 5-year cumulative rates of mortality, restroke and poor outcomes (combined death and further vascular events) were 18, 27 and 37%, respectively. In patients with concurrent lesions, these rates were 31, 41 and 51%, respectively. The corresponding rates were 13, 22 and 31% in patients without concurrent lesions. The risks were highest in the first year after stroke. More deaths (log rank, 16.3; p = 0.0001), restrokes (log rank, 9.71; p = 0.002) and poor outcomes (log rank, 13.87; p = 0.0001) were found among patients with concurrent lesions. The presence of concurrent vascular lesions, advanced age, smoking, hyperlipidemia and previous history of stroke were independent predictors of poor outcomes. CONCLUSIONS: The long-term prognosis of ischemic stroke patients with concurrent atherosclerosis of intracranial and extracranial vessels is poor. They are at high risk of further vascular events or death.

Hemorrhagic cystitis after allogeneic bone marrow transplantation in children: clinical characteristics and outcome.

Hemorrhagic cystitis (HC) is a well-documented adverse event experienced by patients undergoing hematopoietic stem cell transplantation. When severe, HC causes significant morbidity, leads to renal complications, prolongs hospitalization, increases health-care costs, and occasionally contributes to death. We retrospectively studied the medical records of 245 children undergoing an initial allogeneic bone marrow transplantation for malignant disease at St. Jude Children's Research Hospital between 1992 and 1999 to describe the clinical course of HC in all patients and to identify the risk factors for HC in this cohort. Conditioning regimens included cyclophosphamide, cytarabine, and total body irradiation. Grafts from unrelated or mismatched related donors were depleted of T lymphocytes, whereas matched sibling grafts were unmanipulated. All patients received cyclosporine as prophylaxis for graft-versus-host disease. Recipients of grafts from matched siblings also received pentoxifylline or short-course methotrexate. Severe HC developed in 27 patients (11.0%). The median duration of HC was 73 days (range, 5-619 days); 12 patients had ongoing HC at the time of death. In univariate analyses, patients were at increased risk of severe HC if they were male (P =.021) or had received T cell-depleted grafts (P =.017), grafts from unrelated donors (P =.021), a lower total nucleated cell dose (P =.032), or antithymocyte globulin (P =.0446). Multiple regression analysis revealed male sex (beta =.97; P =.027) and unrelated donor graft recipients (beta =.83; P =.039) to be significant factors.

Tumefactive demyelinating lesions by combined perfusion-weighted and diffusion weighted imaging.

Tumefactive demyelinating lesion may sometimes mimic intracranial neoplasm or abscess and pose a diagnostic problem both clinically and radiologically. The diagnosis is even more complicated since multiple sclerosis is relatively uncommon among Chinese and due to low incidence of oligoclonal protein in the cerebrospinal fluid. We present a Chinese lady with tumefactive demyelinating lesion, which mimic cystic neoplasm and cerebral abscess. The use of perfusion and diffusion weighted imaging obviated unnecessary surgical biopsy.

Effect of HLA class I or class II incompatibility in pediatric marrow transplantation from unrelated and related donors.

The degree of histoincompatibility that can be tolerated, and the relative importance of matching at individual HLA class I and class II locus in bone marrow transplantation (BMT) has not been established. We hypothesized that matching for HLA-DR may not be more important than matching for HLA-A or HLA-B in selection of a donor for successful BMT. We retrospectively analyzed the outcomes of 248 consecutive pediatric patients who received allogeneic BMT from related donors (RD, n = 119) or unrelated donors (URD, n = 129). HLA-A and HLA-B were serologically matched, and HLA-DRB1 were identical by DNA typing in 69% of donor-recipient pairs. Most patients (89%) had hematologic malignancies; the rest had aplastic anemia or a congenital disorder. One HLA-A antigen mismatch was associated with a decrease in survival (p = 0.003) and a delay in granulocyte engraftment (p = 0.02) in recipients of RD marrow; as well as a decrease in survival (p = 0.02) and the development of severe acute graft-versus-host disease (GVHD) (p = 0.03) in recipients of URD marrow. One HLA-B antigen mismatch was associated with a decrease in the survival (p = 0.05) and the development of severe GVHD (p = 0.0007) in recipients of RD marrow. One HLA-DRB1 allele mismatch was associated only with a decrease in the survival (p = 0.0003) of recipients of RD marrow. Results of this study suggest that disparity in HLA-A and HLA-B antigens may not be better tolerated than disparity in HLA-DR allele in allogeneic BMT. Further studies are warranted to confirm our results.

A prospective study of elective stenting in unprotected left main coronary disease.

The standard treatment of left main coronary artery (LMCA) disease has been bypass surgery (CABG). Recent reports suggested that stenting of LMCA disease might be feasible. From January 1995 to April 1998, we carried out a prospective study of elective stenting of unprotected LMCA disease to evaluate its immediate and long-term results. Of 61 consecutive patients with unprotected LMCA disease, 6 were excluded. Acute procedural success was 100% for the remaining 55 patients, without any complications such as stent thrombosis, myocardial infarction, CABG, or death. During a mean follow-up of 16.1+/-9.6 months, 11 patients (20%) had symptomatic recurrence, between 2 to 6 months after their procedure. Seven patients underwent CABG, two had repeat intervention, one continued with medical therapy, and one died before planned angiography. There was no late sudden death. Forty-four patients (80%) remained asymptomatic. We conclude that elective stenting may be a safe alternative to CABG in unprotected LMCA disease.

Coronary and circulatory support strategies for percutaneous transluminal coronary angioplasty in high-risk patients.

PTCA is now applied to patients with unstable acute ischemic syndromes, severe multivessel coronary artery disease, and impaired left ventricular function. To minimize the risk during angioplasty, several coronary and systemic circulation support approaches have been developed as adjuncts to high-risk angioplasty. Local coronary support techniques include the perfusion balloon catheter, the coronary stent, directional coronary atherectomy, laser balloon angioplasty, perfluorocarbon coronary perfusion, coronary sinus retroperfusion, and distal coronary hemoperfusion. Systemic circulatory support includes intraaortic balloon counterpulsation, cardiopulmonary support, the hemopump, and left heart partial bypass. These support devices, while associated with significant complications, may ultimately improve the safety of coronary angioplasty and allow its application to those who would otherwise not be candidates for revascularization.

Echocardiographic diagnosis of an aortic root abscess after Mycobacterium fortuitum prosthetic valve endocarditis.

A patient with an aortic root abscess complicating Mycobacterium fortuitum prosthetic endocarditis is described. The correct diagnosis had been made preoperatively by echocardiography and was confirmed subsequently at surgery.

Aneurysmal coronary sinus associated with severe valvular heart disease.

We report a case of aneurysmal coronary sinus complicating severe valvular disease with severe tricuspid regurgitation. Injection in the left superior vena cava outlines the aneurysmal coronary sinus with stasis of the contrast. As this anomaly carries special surgical implication in patients requiring open heart surgery, a correct preoperative diagnosis is mandatory.

Candida right ventricular mural endocarditis complicating indwelling right atrial catheter.

Catheter-associated candidemia is a common problem in immunocompromised patients. A leukemic patient had Candida right ventricular mural endocarditis complicating an indwelling right atrial catheter. To our knowledge, this is the first reported case of Candida right ventricular mural vegetation visualized by two-dimensional echocardiography.

Cardiac tamponade complicating leukaemia: immediate chemotherapy or pericardiocentesis?

Although leukaemic infiltration of the pericardium is frequently observed at post-mortem, clinically evident cardiac tamponade is rare. Two cases of cardiac tamponade complicating leukaemia are presented. One patient had cardiac tamponade as the initial presentation of acute lymphoblastic leukaemia and experienced complete resolution of the pericardial effusion within 6 days after chemotherapy without therapeutic pericardiocentesis. The other patient with chronic myeloid leukaemia developed cardiac tamponade requiring pericardiocentesis as the first sign of acute blastic transformation. The roles of early chemotherapy and pericardiocentesis in managing this complication are discussed.

Myocardial involvement in Churg-Strauss syndrome: the role of endomyocardial biopsy.

A Chinese adult with Churg-Strauss syndrome with prominent cardiac involvement is described. The myocardial impairment initially showed good response to corticosteroid and cyclophosphamide. However, the cardiac status deteriorated later despite the absence of disease activity elsewhere. Endomyocardial biopsy was performed to determine the possibility of isolated myocardial relapse in case additional immunosuppression would be beneficial. Histology of the endomyocardial biopsy revealed myocardial fibrosis. Since cardiac involvement is the major cause of mortality in this condition and delayed treatment can lead to intractable cardiac failure, we advocate that endomyocardial biopsy should be performed more liberally and possibly serially to assess the disease activity in the myocardium. Immunosuppression may then be adjusted. To our knowledge, the occurrence of Churg-Strauss syndrome in Chinese has not been reported in the English literature.