Pilot study of modified LMB-based therapy for children with ataxia-telangiectasia and advanced stage high grade mature B-cell malignancies.

Children with ataxia-telangiectasia (A-T) and cancer have a poorer prognosis due in part to increased treatment-related toxicity. We piloted a curative intent approach in five children with A-T who presented with advanced stage (III, n = 2; IV, n = 3) B-NHL (diffuse large B-cell lymphoma, n = 4; Burkitt leukemia, n = 1) using a modified LMB-based protocol. Two achieved sustained CCR (one, CCR at 6 years; one, pulmonary death after 3 years in CCR). Two died from toxicity during induction and 1 failed induction with progressive disease. Novel therapeutic approaches which overcome drug resistance and are less toxic are needed for children with A-T and B-NHL.

Results of treatment of advanced-stage lymphoblastic lymphoma at St Jude Children's Research Hospital from 1962 to 2002.

BACKGROUND: Reliable prognostic factors have not been established for advanced-stage pediatric lymphoblastic lymphoma (LL). We analyzed treatment outcomes and potential risk factors in children and adolescents with advanced-stage LL treated over a 40-year period. PATIENTS AND METHODS: From 1962 through 2002, 146 patients (99 boys and 47 girls) with stage III (n = 111) or stage IV (n = 35) LL were treated at St Jude Children's Research Hospital. The five treatment eras were 1962-1975 (no protocol), 1975-1979 (NHL-75), 1979-1984 (Total 10 High), 1985-1992 (Pediatric Oncology Group protocol), and 1992-2002 (NHL13). Age at diagnosis was <10 years in 65 patients and ≥10 years in 81. RESULTS: Outcomes improved markedly over successive treatment eras. NHL13 produced the highest 5-year event-free survival (EFS) estimate (82.9% ± 6.1% [SE]) compared with only 20.0% ± 8.0% during the earliest era. Treatment era (P < 0.0001) and age at diagnosis (<10 years versus ≥10 years, P = 0.0153) were independent prognostic factors, whereas disease stage, lactate dehydrogenase level, and presence of a pleural effusion were not. CONCLUSIONS: Treatment era and age were the most important prognostic factors for children with advanced-stage LL. We suggest that a better assessment of early treatment response may help to identify patients with drug-resistant disease who require more intensive therapy.

Frequent mutations in SH2D1A (XLP) in males presenting with high-grade mature B-cell neoplasms.

X-linked lymphoproliferative syndrome (XLP) is caused by mutations in SH2D1A, and is associated with overwhelming infectious mononucleosis, aplastic anemia, hypogammaglobulinemia, and B-cell lymphomas. However, the frequency of SH2D1A mutations in males who present with B NHL is unknown. Five cases of XLP were diagnosed among 158 males presenting with B NHL (approximately 3.2%). Four of the patients had two episodes of B NHL and one had a single episode of B NHL followed by aggressive infectious mononucleosis. Prospective screening for XLP in males with B-cell lymphoma at the time of initial diagnosis should be considered.

Efficacy of high-dose methotrexate, ifosfamide, etoposide and dexamethasone salvage therapy for recurrent or refractory childhood malignant lymphoma.

BACKGROUND: Children with recurrent or refractory malignant lymphoma generally have a poor prognosis. There is a need for new active drug combinations for this high-risk group of patients. PATIENTS AND METHODS: This study evaluated the activity and toxicity of the methotrexate, ifosfamide, etoposide and dexamethasone (MIED) regimen for childhood refractory/recurrent non-Hodgkin's lymphoma (NHL) or Hodgkin's lymphoma (HL). From 1991 through 2006, 62 children with refractory/recurrent NHL (n = 24) or HL (n = 38) received one to six cycles of MIED. Based on MIED response, intensification with hematopoietic stem cell transplantation (HSCT) was considered. RESULTS: There were 10 complete (CR) and 5 partial responses (PR) among the 24 children with NHL [combined response rate, 63%; 95% confidence interval (CI) 38% to 73%]. There were 13 CR and 18 PR among the 37 assessable children with HL (combined response rate, 84%; 95% CI, 68% to 94%). Although 59% courses were associated with grade IV neutropenia, treatment was well tolerated and without toxic deaths. CONCLUSIONS: MIED is an effective regimen for refractory/recurrent childhood malignant lymphoma, permitting a bridge to intensification therapy with HSCT.

Diffuse CNS vasculopathy with chronic Epstein-Barr virus infection in X-linked lymphoproliferative disease.

We report a patient with X-linked lymphoproliferative disease (XLP) who developed multiple central nervous system (CNS) manifestations of Epstein-Barr virus infection. XLP, or Duncan syndrome, is a rare inherited disorder characterized by the inability to clear Epstein-Barr virus infection. In addition to Epstein-Barr virus encephalitis, CNS lymphoproliferative disease, and lymphoma, this patient also developed MR angiographic evidence of diffuse fusiform aneurysmal dilation of intracranial vessels.

Cytogenetic findings in mantle cell lymphoma cases with a high level of peripheral blood involvement have a distinct pattern of abnormalities.

We compared conventional cytogenetic findings in mantle cell lymphomas (MCLs) having an absolute peripheral lymphocytosis of more than 10,000/microL (>10 x 10(9)/L) at diagnosis ("leukemic"; n = 30) with those in cases having no or minimal lymphocytosis ("nodal"; n = 19). Only cases positive for t(11;14) were included for study. Forty-six cases (94%) had abnormalities in addition to t(11;14). The most frequent abnormalities involved chromosome 13 (26 cases [53%]), followed by chromosomes 1, 3, 7, 8, 9, 10, 12, 15, 17, and 21 (11-18 cases [22%-37%]). There was no difference in the number of aberrations between the 2 groups. Abnormalities of chromosomes 17, 21, and 22 were more frequent, and breakpoints involving 8q24, 9p22-24, and 16q24 were found exclusively in leukemic MCL. Chromosome 17 aberrations involved were structural (breakpoints involving 17p13, 17p11.2, 17q) in leukemic MCL but were only numeric in nodal MCL. Thus, leukemic MCL differs from nodal MCL in their cytogenetic profiles, which may contribute to the clinical presentation.

ETV6-RUNX1-positive childhood acute lymphoblastic leukemia: improved outcome with contemporary therapy.

ETV6-RUNX1 fusion is the most common genetic aberration in childhood acute lymphoblastic leukemia (ALL). To evaluate whether outcomes for this drug-sensitive leukemia are improved by contemporary risk-directed therapy, we studied clinical features, response and adverse events of 168 children with newly diagnosed ETV6-RUNX1-positive ALL on St Jude Total Therapy studies XIIIA (N=36), XIIIB (N=38) and XV (N=94). Results were compared with 494 ETV6-RUNX1-negative B-precursor ALL patients. ETV6-RUNX1 was associated with age 1-9 years, pre-treatment classification as low risk and lower levels of minimal residual disease (MRD) on day 19 of therapy (P<0.001). Event-free survival (EFS) or overall survival (OS) did not differ between patients with or without ETV6-RUNX1 in Total XIIIA or XIIIB. By contrast, in Total XV, patients with ETV6-RUNX1 had significantly better EFS (P=0.04; 5-year estimate, 96.8±2.4% versus 88.3±2.5%) and OS (P=0.04; 98.9±1.4% versus 93.7±1.8%) than those without ETV6-RUNX1. Within the ETV6-RUNX1 group, the only significant prognostic factor associated with higher OS was the treatment protocol Total XV (versus XIIIA or XIIIB) (P=0.01). Thus, the MRD-guided treatment schema including intensive asparaginase and high-dose methotrexate in the Total XV study produced significantly better outcomes than previous regimens and demonstrated that nearly all children with ETV6-RUNX1 ALL can be cured.

Long-term results of St Jude Total Therapy Studies 11, 12, 13A, 13B, and 14 for childhood acute lymphoblastic leukemia.

We analyzed the long-term outcome of 1011 patients treated in five successive clinical trials (Total Therapy Studies 11, 12, 13A, 13B, and 14) between 1984 and 1999. The event-free survival improved significantly (P=0.003) from the first two trials conducted in the 1980s to the three more recent trials conducted in the 1990s. Approximately 75% of patients treated in the 1980s and 80% in the 1990s were cured. Early intensive triple intrathecal therapy, together with more effective systemic therapy, including consolidation and reinduction treatment (Studies 13A and 13B) as well as dexamethasone (Study 13B), resulted in a very low rate of isolated central nervous system (CNS) relapse rate (<2%), despite the reduced use of cranial irradiation. Factors consistently associated with treatment outcome were age, leukocyte count, immunophenotype, DNA index, and minimal residual disease level after remission induction treatment. Owing to concerns about therapy-related secondary myeloid leukemia and brain tumors, in our current trials we reserve the use of etoposide for patients with refractory or relapsed leukemia undergoing hematopoietic stem cell transplantation, and cranial irradiation for those with CNS relapse. The next main challenge is to further increase cure rates while improving quality of life for all patients.

Effective treatment of advanced-stage childhood lymphoblastic lymphoma without prophylactic cranial irradiation: results of St Jude NHL13 study.

There has been a steady improvement in cure rates for children with advanced-stage lymphoblastic non-Hodgkin's lymphoma. To further improve cure rates whereas minimizing long-term toxicity, we designed a protocol (NHL13) based on a regimen for childhood T-cell acute lymphoblastic leukemia, which features intensive intrathecal chemotherapy for central -nervous system-directed therapy and excludes prophylactic cranial irradiation. From 1992 to 2002, 41 patients with advanced-stage lymphoblastic lymphoma were enrolled on the protocol. Thirty patients had stage III and 11 had stage IV disease. Thirty-three cases had a precursor T-cell immunophenotype, five had precursor B-cell immunophenotype and in three immunophenotype was not determined. Out of the 41 patients, 39 (95%) achieved a complete remission. The 5-year event-free rate was 82.9+/-6.3% (s.e.), and 5-year overall survival rate was 90.2+/-4.8% (median follow-up 9.3 years (range 4.62-13.49 years)). Adverse events included two induction failures, one death from typhlitis during remission, three relapses and one secondary acute myeloid leukemia. The treatment described here produces high cure rates in children with lymphoblastic lymphoma without the use of prophylactic cranial irradiation.

Increased risk for CNS relapse in pre-B cell leukemia with the t(1;19)/TCF3-PBX1.

To evaluate the impact of contemporary therapy on the clinical outcome of children with pre-B acute lymphoblastic leukemia (ALL) and the t(1;19)/TCF3/PBX1, we analyzed 735 patients with B-cell precursor ALL treated in four successive protocols at St Jude Children's Research Hospital. The 41 patients with the t(1;19) had a comparable event-free survival to that of the 694 patients with other B-cell precursor ALL (P=0.63; 84.2+/-7.1% (s.e.) vs 84.0+/-1.8% at 5 years). However, patients with the t(1;19) had a lower cumulative incidence of any hematological relapse (P=0.06; 0 vs 8.3+/-1.2% at 5 years) but a significantly higher incidence of central nervous system (CNS) relapse (P<0.001; 9.0+/-5.1% vs 1.0+/-0.4% at 5 years). In a multivariate analysis, the t(1;19) was an independent risk factor for isolated CNS relapse. These data suggest that with contemporary treatment, patients with the t(1;19) and TCF3/PBX1 fusion have a favorable overall outcome but increased risk of CNS relapse.

[Clinical outcome of lupus nephritis in Constanta County]. / Studiu epidemiologic descriptiv al insuficientei renale cronice în Judetul Constanta.

UNLABELLED: The epidemiology of chronic renal failure (CRF) and renal replacement therapy (RRT) is under continuous surveillance all over the world. In Constanja county, as well as in other Romanian regions, an increase in the prevalence of patients on RRT (dialysis or transplantation) has been observed during the recent years. AIM: To determine the prevalence of chronic renal failure in Constanta county, in variable stages of evolution, as well as monitoring of renal replacement therapy in our region. METHODS: This epidemiological study is based on data collected from patients hospitalized in the 1st Clinical Department of Internal Medicine, or from other Department of the Emergency Hospital, regular periodic visits of predialytic patients in the Ambulatory Nephrology Cabinet and from the Hemodialysis Center of Constanta, in the interval of time 1st January 2003-30 June 2005. A total group of 585 patients were evaluated till the end of our study. The study was based upon the available clinical and biochemical data, obtained during routine clinical care. RESULTS: The disease affects more frequently the male gender and the young to middle-aged population. Because 56.88% of renal patients are in a predialytic phase, it is obvious that a large population group will need in the proximate future places for renal replacement therapy. CONCLUSION: CRF has a high incidence in Constanta county; the rate detected during our study was 82.1 cases per 100,000 population. Chronic glomerulonephritis and pyelonephritis, followed by diabetic nephropathy were the most frequently reported causes of renal failure. The most frequent comorbid associated conditions were cardiovascular diseases, followed by infections and bone diseases, in both predialytic and dialytic/transplanted population. Almost 10% of our patients died during the study. The most frequent causes of death were: cardiogenic shock, arrhythmias, cerebral strokes and sepsis.

[Specifics of the blood supply of the sinoatrial node]. / Particularitati ale vascularizatiei nodulului sino-atrial.

The present study aims to identify the heart nodal system blood supply sources and especially those of the sinoatrial node. It included 50 unpreserved and preserved human hearts from subjects of both sexes (40 males and 10 females) aged 12 to 68, of Romanian (42) and non-Romanian origin (8). The used denominations are those recommended by DiDio & Wakefield, based on splitting of the atrial walls into four quadrants (right and left, both anterior and posterior) which are further divided into three parts (medial, middle and lateral). We used special dissection techniques and plastic mass injections followed by corrosion. Our results confirm the opinion shared by most authors, in favour of the predominance of the origin of sinoatrial node artery from the right coronary artery. The sinoatrial node was supplied by a unique source represented by the right coronary artery in 37 cases (74%) and by the circumflex artery in 8 cases (16%), and by a double source represented by two branches of the right coronary artery in 2 cases (4%) and of both coronary arteries in 3 cases (6%). The direct arterial branches to the sinoatrial node were represented mainly by the right anteromedial atrial artery with origin from the right coronary artery level with the medial third of the right anterior quadrant of the atrial wall. From the left coronary system, the left anteromedial artery is the one responsible with the sinoatrial node supply; the source is the circumflex artery and its origin is the medial third of the left anterior quadrant. Contrary to DiDio et al., we found in addition to the mainly unilateral blood supply, the bilateral one. We didn't find any case with a sinoatrial node artery originating from the trunk of the left coronary artery, or with an extracardiac origin. We may state there are no significant differences of the origin and distribution of the sinoatrial node artery related to sex or country of origin. Thus, we cannot fully confirm the theories about the influence of the general variation factors on the arterial origin. The atherosclerotic or thrombotic obstruction of the sinoatrial node artery may induce severe heart rhythm disturbances or even sudden death.

[Checking a model of cardiac segmentation of the left half of the heart]. / Verificarea unui model de segmentatie cardiaca la nivelul hemicordului stâng.

The present work is aimed to study the distribution of the coronary arteries to the left ventricle; 120 fresh and prepared human hearts harvested from healthy individuals of both sexes aged 4 to 78 have been used. The denomination of the cardiac segments is the one used by Liberato, Didio & Rodrigues in 1983. Starting from this model, we sought for sustaining or invalidating arguments. We used special dissection techniques, radiographs of radioopaque substances injected hearts, and corroded after plastic substances injection organs. Each ventricular segment in the left ventricle is supplied by an arterial branch (called "segmental") of the coronary arteries (left coronary artery in most of cases). The anterior interventricular branch segment (I SV or SVIA) is the area of the heart supplied by the arterial branch with the same name, originating in the left coronary artery. Depending on its length, we found a small segment (the branch did not pass over the apex of the heart, thus supplying the sternocostal surface of the heart only) in 39 cases (32.5%), and a big segment (the artery ended on the diaphragmatic surface of the heart, in the posterior interventricular groove) in 81 cases (67.5%). The lateral branch segment (II SV or SVL) includes in most of cases (78%) a part of the pulmonary wall of he left ventricle, up to the apex (Liberato et al. found a percent of 66). In the rest of cases (22%) it additionally includes a part of the diaphragmatic wall of the left ventricle. The left marginal branch segment (III SV or SVM) is a big one when it includes parts of the pulmonary and diaphragmatic walls of the left ventricle and part of the diaphragmatic wall of the right ventricle; it is middle-sized when it includes parts of the left and diaphragmatic walls of the left ventricle; it is considered small when it extends over parts of the left and diaphragmatic walls of the left ventricle adjacent to the pulmonary surface (36%, 40% and 24% of cases, respectively). The posterior ventricular branch segment (IV SV or SVP) includes: a small part of the diaphragmatic wall of the left ventricle close to the pulmonary surface--52 cases (43.3%); the superior half of the diaphragmatic wall of the left ventricle up to the posterior interventricular septum--19% of cases; the superior third of the left ventricle, up to the septum--20% of cases; the superior part of the diaphragmatic wall of both ventricles and the superior part of the septum--13.6% of cases. The segments are separated by intersegmental planes whose position depends of the degree of development of each cardiac segment. No significant differences were observed in what concerns the extension of the cardiac segments and the position of intersegmental planes in relation to sex. The segments can be totally independent or slightly dependent to the blood supply of the neighbouring segments.

[Epidemiologic aspects of sudden death in the Constanta District]. / Particularitati epidemiologice ale mortii subite in judetul Constanta.

This study is aimed to clarify some aspects of the cardiac sudden death (CSD) in the context of the general pathology. 5842 cases were taken into study, representing the total number of autopsies performed in the Forensic Department of Constanta District between 1997-2002 (subjects of both sexes aged 6 months to 82 years). Sudden death represents 80% of the non-violent death cases. We found 1563 cases of sudden death, out of which 891 were CSD (57%). The yearly distribution of the CSD cases was: 1997 - 205 cases (58.23%), 1998 - 164 (56%), 1999 - 161 (60%), 2000 - 121 (67.6%), 2001 - 98 (52.4%), 2002 - 142 (50.17%). Coronary atherosclerosis was the cause of 78% of the CSD. They are followed by far by other causes: respiratory (24.3%), meningo-cerebral (5.05%), digestive (2.3%), endocrine (1.85%), infectious (1.6%), the syndrome of the child sudden death (1.28%), renal (0.64%), neurological (0.57%), allergic (0.9%), hematological (0.32%), the syndrome of the sportsmen sudden death (0.32%). These figures are age-dependent: between 45-65 years of age the cardiovascular/respiratory causes ratio is of 5/1 ; it decreases to lesser ages to become inversed (1/2). The ratio to the meningo-cerebral causes is of 25/1 and largely decreases so that over 70 years of age it becomes usually 2/1 and sometimes 1/1.

Leukemic mantle cell lymphoma: clinical and pathologic spectrum of twenty-three cases.

Twenty-three patients with marked leukemic involvement by mantle cell lymphoma (MCL) are described. Each patient had an absolute lymphocyte count more than 10 x 10(9)/L. The diagnosis of MCL was supported by compatible immunophenotypic findings and the t(11;14)(q13;q32) in all cases. Morphologically, these cases exhibited a spectrum of findings that we divided into two groups using a cutoff of 20% large or blastoid cells (log rank test, P =.004). Patients with small-cell (<20%) morphologic features survived longer than patients with large/blastoid (> or =20%) morphologic features, (P =.003, log rank test). The most common additional karyotypic abnormality identified in this study involved chromosome 17, in 13 of 23 (56.5%) cases, which correlated with p53 overexpression but not with cytologic features. We conclude that cytologic features of MCL predict the prognosis of patients with marked leukemic involvement. Chromosome 17 abnormalities are common in leukemic MCL, may be involved in pathogenesis, and are associated with p53 expression.