Biomedical subjects

J J Shuster

Publications and source records attributed to J J Shuster.

At least 37 records · Page 2Linked to original sources

PubMed1999

Lymph node sampling in localized neuroblastoma: a Pediatric Oncology Group study.

BACKGROUND/PURPOSE: Lymph node (LN) sampling was required by the Pediatric Oncology Group (POG) staging for neuroblastoma and currently is required as a part of the International Neuroblastoma Staging System (INSS). This retrospective study of planned lymph node sampling in patients with localized neuroblastoma was carried out with the intent of assisting surgeons in carrying out this procedure. The report documents the POG experience where LN, both uninvolved and involved with tumor, were found based on site of primary. METHODS: From 391 patients with localized neuroblastoma of the abdomen, chest, and neck, 238 patients had LN sampling at the primary operation, and these patients constitute the major part of the study. In addition, 89 patients had a carefully documented search for LN, and 64 had neither search nor biopsy. The operative note, pathology report, and surgical study sheet were used in the 238 patients based on the site of the primary tumor to determine which nodal groups or basins underwent biopsy, and in which groups tumor was found. RESULTS: The pattern of drainage, based on the primary site of abdominal tumors, favored an arterial rather than venous pathway. Primary tumors and metastatic LN were more numerous on the left side. The abdominal drainage followed three pathways: (1) infrarenal tumors from the left and midline were associated with paraaortic LN; (2) right infrarenal tumors were associated with LN in the paracaval basin; (3) with suprarenal primaries and with both adrenals, the superior mesenteric-portal-celiac basins were most productive for nodal sampling. Tumor was found most frequently in the left adrenal-renal basin and in the paraaortic basin. The actual number of LN sampled in a single case varied from 1 to 19 LN, with a mean number of LN based on stage and primary from one to seven LN. The tumor spread in LN was consistent with a "watershed" course, but this was not statistically significant. Patients for whom LN were sought had a better outcome, contrasting with the patients in whom LN were not sought or in whom nodal sampling was not possible. CONCLUSIONS: The experience in this study is consistent with previous descriptions of the lymphatic drainage of the retroperitoneal area. Delineation of the various basins as they relate to the site of the primary tumor should assist the surgeon in lymph node sampling. The role of LN involvement still remains unclear in the light of current studies of biological factors and histopathology as determinants of "risk groups." It is hoped that this study will enable ongoing and future studies to clarify this problem. The adult experience with breast cancer and with melanoma has indicated a continued importance of anatomic factors (including LN status) along with biological factors.

Abdominal Neoplasms↗

PubMed1999

Group sequential designs for phase II trials with historical controls.

Two-step tests based on historical control data are proposed for detecting different means when experimental and control populations are normally distributed with possibly different known variances. The results readily extend to the case where the control and experimental data are dichotomous. Provisions for early acceptance and early rejection are included.

Analysis of Variance↗

PubMed1999

Significance of commonly used prognostic factors differs for children with T cell acute lymphocytic leukemia (ALL), as compared to those with B-precursor ALL. A Pediatric Oncology Group (POG) study.

T cell acute lymphocytic leukemia (T-ALL) and B-precursor ALL differ significantly in the clinical characteristics of the patients at presentation and in laboratory-defined characteristics of the leukemic cells. We assessed for pediatric patients with T-ALL the relative importance of prognostic factors previously demonstrated to predict outcome in B-precursor ALL. Presenting clinical and laboratory features were correlated with outcome for 441 children 12 months to 21 years of age with previously untreated T-ALL, registered on the Pediatric Oncology Group (POG) T3 protocol between 1986 and 1992. These T-ALL prognostic factor analyses were then compared to similar analyses for 1993 patients with B-precursor ALL enrolled during the same time period on the POG ALinC 14 protocol. Quantitative interaction between phenotype and each prognostic factor was studied to determine the relative importance of the prognostic factor for each of the two major immunophenotypes. We also analyzed the importance of maturational stage as a T-ALL prognostic factor, using a modified Ludwig definition of maturational stage. We conclude that several of the clinical and laboratory prognostic factors, which are used reliably for B-precursor ALL, are much less predictive in T-ALL (ie age, WBC, consensus risk group, hyperdiploidy, presence of trans- locations and CALLA expression). There was no significant difference between the phenotypes in the prognostic importance of race or gender. Our data demonstrate a significant difference in outcome among the three maturational stages of T-cell ALL, with the intermediate group faring best. Using traditional risk group criteria to stratify patients with T-ALL for therapy may not be appropriate.

Adolescent↗

PubMed1999

Childhood acute lymphoblastic leukemia with the MLL-ENL fusion and t(11;19)(q23;p13.3) translocation.

PURPOSE: To determine the molecular characteristics, clinical features, and treatment outcomes of children with acute lymphoblastic leukemia (ALL) and the t(11;19)(q23,p13.3) translocation. PATIENTS AND METHODS: A retrospective analysis of leukemic cell karyotypes obtained from patients with new diagnoses of ALL who were treated at St. Jude Children's Research Hospital or by the Pediatric Oncology Group was performed to identify cases with the t(11;19)(q23;p13.3) translocation. Molecular analyses were performed on these cases to determine the status of the MLL gene and the presence of the MLL-ENL fusion transcript. RESULTS: Among 3,578 patients with ALL and successful cytogenetic analysis, we identified 35 patients with the t(11;19)(q23;p13.3) translocation: 13 infants and 11 older children had B-precursor leukemia, whereas 11 patients had a T-cell phenotype. Although all of the cases examined had MLL rearrangements and MLL-ENL fusion transcripts, outcome varied according to age and immunophenotype. Among B-precursor cases, only two of the 13 infants remain in complete remission, compared with six of the 11 older children. Most strikingly, no relapses have occurred among B-precursor patients 1 to 9 years of age or among T-cell patients. CONCLUSION: Although MLL gene rearrangements are generally associated with a dismal outcome in ALL, two distinct subsets with MLL-ENL fusions have an excellent prognosis. Our results suggest that patients with this genetic abnormality who have T-cell ALL or are 1 to 9 years of age should not be considered candidates for hematopoietic stem-cell transplantation during their first remission.

Adolescent↗

PubMed1999

Treatment of localized primary non-Hodgkin's lymphoma of bone in children: a Pediatric Oncology Group study.

PURPOSE: The treatment of primary lymphoma of bone (PLB) in children has traditionally included radiotherapy to the primary site; more recently, it has included systemic chemotherapy. Because of concern about the untoward effects of treatment in a disease that is curable, we attempted to determine whether radiotherapy can be safely excluded from treatment. PATIENTS AND METHODS: The results of three consecutive Pediatric Oncology Group (POG) studies were examined to determine the impact on outcome of radiotherapy as adjunctive treatment in children and adolescents receiving chemotherapy for early-stage primary lymphoma of bone. RESULTS: From 1983 to 1997, 31 patients with localized PLB were entered onto POG studies of early-stage non-Hodgkin's lymphoma (NHL). Between 1983 and 1986, seven patients were treated with 8 months of chemotherapy with irradiation (XRT) of the primary site. After 1986, patients were treated without XRT; four received 8 months of chemotherapy, and 20 received 9 weeks of chemotherapy. Primary sites were the femur (nine), tibia (eight), mandible (five), mastoid (one), maxilla (one), zygomatic arch (one), rib (one), clavicle (one), scapula (one), ulna (one), talus (one), and calcaneous (one). Histologic classification revealed 21 cases of large cell lymphoma, five cases of lymphoblastic lymphoma, two cases of small, noncleaved-cell lymphoma, and three cases of NHL that could not be classified further. One patient relapsed at a distant site 22 months after completion of therapy. There have been no deaths. CONCLUSION: Localized PLB is curable in most children and adolescents with a 9-week chemotherapy regimen of modest intensity, and radiotherapy is an unnecessary adjunct.

Adolescent↗

PubMed1998

A multidisciplinary study investigating radiotherapy in Ewing's sarcoma: end results of POG #8346. Pediatric Oncology Group.

PURPOSE: To determine if involved field radiation (IF) is equivalent to standard whole bone radiation (SF) in local tumor control; to establish patterns of failure following treatment; and to determine response, event-free survival (EFS), and overall survival rates from multidisciplinary therapy in Ewing's sarcoma. METHODS AND MATERIALS: Between 1983 and 1988, 184 children with Ewing's sarcoma were enrolled onto Pediatric Oncology Group 8346 (POG 8346). A total of 178 (97%) met eligibility criteria; 6 had pathology other than Ewing's sarcoma. Induction chemotherapy of cyclophosphamide/doxorubicin (adriamycin )(C/A) x 12 weeks was followed by local treatment either surgery or radiation therapy and C/A, dactinomycin, and vincristine for 50 weeks. Resection was advised for patients with small primary tumors if accomplished without functional loss. Forty patients were randomized to receive SF, whole bone radiation to 39.6 Gy plus a 16.2 Gy boost (total 55.8 Gy) or IF to 55.8 Gy, and the remainder were assigned to IF radiation. RESULTS: Of 178 eligible patients, 141 (79%) had localized disease and 37 (21%) had metastases at presentation. Their 5-year EFS was 51% (SE 5%) and 23% (SE 7%) respectively. The response rate to induction chemotherapy was 88% (28% complete, 60% partial), but after radiotherapy the response rate increased to 98%. Thirty-seven of the localized patients underwent resection, of whom 16 (43%) required postoperative radiotherapy; the 5-year EFS of these surgical patients was 80% (SE 7%). The remaining 104 localized patients were eligible for randomization or assignment to receive radiotherapy; the 5-year EFS of these patients was 41% (SE 5%), with no significant difference in EFS between those randomized to SF vs. IF. Site of primary tumor correlated with 5-year EFS: distal extremity 65% (SE 8%), central 63% (SE 10%), proximal extremity 46% (SE 8%), and pelvic-sacral 24% (SE 10%) (p=0.004). Initial tumor size did not correlate significantly with EFS. Patterns of failure among the 141 localized patients revealed 23% of patients experienced a local failure, while 40% had a systemic failure. The 5-year local control rate for the surgical patients +/- postoperative radiotherapy was 88% (SE 6%), while for the patients undergoing radiotherapy alone it was 65% (SE 7%). There was no difference in local control between those randomized to SF vs. IF. The 5-year local control rate for the patients with pelvic-sacral tumors was 44% (SE 15%), significantly worse than the local control rates for those with central tumors 82% (SE 8%), distal extremity 80% (SE 8%), or proximal extremity 69% (SE 9%) (p=0.023). However, quality of radiotherapy correlated with outcome. Patients who had appropriate radiotherapy had a 5-year local control of 80% (SE 7%), while those with minor deviations had 5-year local control of 48% (SE 14%), and those with major deviations had a local control of only 16% (SE 15%) (p=0.005). The local failure was within an irradiated volume in 62% of patients, outside the irradiated volume in 24% of cases, while the precise location could not be determined in the remaining 14%. CONCLUSIONS: As most failures in Ewing's sarcoma are systemic, improved EFS requires more effective systemic chemotherapy. Adequate IF radiotherapy requires treatment to appropriate volumes as defined by MRI imaging and full radiation doses. Pretreatment review of radiologic images with a musculoskeletal radiologist to determine appropriate tumor volumes, as well as use of conformal radiotherapy techniques are important for improved outcome.

Adolescent↗

PubMed1998

Modelling cure rates using the Gompertz model with covariate information.

We extend the modified Gompertz hazard function, first used by Cantor and Shuster for estimation of cure rates from pediatric clinical trials, by including covariate effects. The extended model provides a convenient method for estimation of the cure rate as a function of treatments and covariates.

Algorithms↗

PubMed1998

E2A-PBX1 chimeric transcript status at end of consolidation is not predictive of treatment outcome in childhood acute lymphoblastic leukemias with a t(1;19)(q23;p13): a Pediatric Oncology Group study.

A t(1;19)(q23;p13) is detected cytogenetically in approximately 5% of childhood acute lymphoblastic leukemias (ALLs) and its presence has been associated with an increased risk of relapse in several previously-completed Pediatric Oncology Group (POG) clinical trials. The t(1;19) fuses E2A to PBX1 in more than 95% of cases and this molecular abnormality can be reliably identified by polymerase chain reaction (PCR)-mediated amplification of E2A-PBX1 chimeric mRNAs. We used a nested PCR assay, which reproducibly detected a 10(4)- to 10(5)-fold dilution of t(1;19)+ into t(1;19)- cells, to evaluate minimal residual disease (MRD) in 48 children with t(1;19)+ ALL enrolled in POG clinical trials for lower (POG 9005) and higher (POG 9006) risk ALL. Peripheral blood (PB) and bone marrow (BM) samples were collected prospectively at the end of consolidation (weeks 25 and 31 after end of induction) and the presence or absence of PCR-detectable MRD was correlated with clinical outcome. Overall, 41 of 148 (28%) samples were PCR+. Of the 65 time points with informative results from both PB and BM, PCR results were concordant for 51 pairs (10 PB+/BM+, 41 PB-/ BM-) and discordant for 14 (5 PB+/BM-, 9 PB-/BM+), indicating that assessment of only PB or only BM can inaccurately classify some PCR+ cases as PCR-. There were no significant differences in event-free survival between PCR+ and PCR- patients. We conclude that qualitative detection of MRD by amplification of E2A-PBX1 chimeric mRNAs at the end of consolidation was not significantly predictive of outcome for children treated on POG 9005/9006 and that such results should not be used to alter therapy for patients with t(1;19)+ ALL.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1998

Publishing clinical trials and dealing with external comparisons.

This brief note is designed to provide research teams that are involved with the publication of clinical trials in peer-reviewed medical journals with a reference for the rebuttal of referees' criticism that your results are in some way inferior overall to those of others. In these reviewers' eyes, a trial that shows less benefit than other trials has no public health benefit, and hence they recommend rejection. In fact, such policies lead to publication bias, the systematic overestimation of benefits of therapy in the published literature.

Clinical Trials as Topic↗

PubMed1998

Immature teratomas in children: pathologic considerations: a report from the combined Pediatric Oncology Group/Children's Cancer Group.

Pediatric germ cell tumors (n = 135) with a major component of immature teratoma (IT) registered on Pediatric Oncology Group/Children's Cancer Group treatment protocols from 1990 to 1995 were reviewed. Sixty cases were pure IT with no malignant component and 75 were mixed tumors with a major component of IT. Foci of yolk sac tumor (YST) were present in all 75 mixed tumors; additional malignant components were present in 15. The IT component was as follows: 47% grade 3, 29% grade 2, 24% grade 1. There were no significant correlations between tumor grade and patient age by specific subsets or overall (all p > 0.10). Significant correlations were detected between stage and the presence of foci of YST (p = 0.0145) and grade and the presence of foci of YST (p < 0.001). Serum alpha-fetoprotein concentrations were elevated at diagnosis in 96% of ovarian tumors with foci of YST and were mildly elevated (< 60 ng/dL) in only 16% of tumors without YST. Overall 2- to 6-year survival rate was 96% and was related to the presence of YST. Central pathologic review revealed aspects of morphologic diagnosis that were most frequently misinterpreted by contributing pathologists. These included the classification of differentiating tissues as immature and the failure to recognize two well-differentiated patterns of YST (the hepatoid pattern resembling fetal liver and the well-differentiated glandular pattern resembling fetal lung or intestine). Such foci were often overlooked. The authors conclude that the presence of microscopic foci of YST, rather than the grade of IT, per se, is the only valid predictor of recurrence in pediatric IT at any site.

Child, Preschool↗

PubMed1998

Acute neurotoxicity in children with B-precursor acute lymphoid leukemia: an association with intermediate-dose intravenous methotrexate and intrathecal triple therapy--a Pediatric Oncology Group study.

PURPOSE: To describe the incidence of acute neurotoxicity (NT) in children with lower risk B-precursor acute lymphoid leukemia (ALL) treated with intermediate-dose methotrexate (MTX) or divided dose oral MTX with or without intravenous (i.v.) mercaptopurine (MP) and extended intrathecal triple therapy. PATIENTS AND METHODS: Thirteen hundred four patients were entered onto Pediatric Oncology Group (POG) 9005, a randomized phase III trial, between January 11, 1991 and September 1, 1994. After remission induction, patients were randomized to one of three 24-week intensification schedules: regimen A, MTX 1,000 mg/m2 i.v. infused over 24 hours and MP 1,000 mg/m2 i.v. infused over 6 hours; regimen B, low-dose repetitive MTX 30 mg/m2 orally every 6 hours for six doses and i.v. MP; or regimen C, i.v. MTX alone. Intensification was given every 2 weeks for 12 courses. CNS prophylaxis was age-adjusted intrathecal MTX (ITM). In August 1992, the CNS prophylaxis was changed to age-adjusted triple intrathecal therapy (TIT). Reports of grades 3 and 4 acute NT were reviewed. RESULTS: Acute NT was reported in 95 of 1,218 (7.8%) eligible patients treated on POG 9005. The incidence by regimen was regimen A, 46 of 543 patients (8.3%); regimen B, 13 of 354 patients (3.7%); and regimen C, 36 of 321 patients (11.2%) (P < .001). The majority of events were seizures and the median number of days to first occurrence of symptomatic NT after ITM or TIT was 10 to 11 days. Computed tomography (CT) or magnetic resonance imaging (MRI) evidence consistent with leukoencephalopathy (LE), with or without the presence of cerebral calcifications, was observed in 75% and 77.1 % of symptomatic patients treated on regimens A and C, respectively, but in only 15.4% of symptomatic patients treated on regimen B (P < .001). Factors associated with an increased incidence of NT included increased cumulative exposure with repeated i.v. MTX (regimens A and C v B), increased MTX-leucovorin (LCV) ratio (regimens A and C v B), and choice and timing of TIT therapy. The use of i.v. MP during intensification did not appear to contribute to these complications. The switch to TIT CNS prophylaxis was associated with an inferior overall 4-year continuous complete remission (CCR) (P=.031) when compared with ITM. CONCLUSION: Intensification with repeated i.v. MTX in the setting of low-dose LCV rescue was associated with a higher risk for acute NT and LE, especially in patients who received concomitant TIT. The long-term consequences for affected patients remain unknown.

Acute Disease↗

PubMed1998

Consolidation therapy with antimetabolite-based therapy in standard-risk acute lymphocytic leukemia of childhood: a Pediatric Oncology Group Study.

PURPOSE: To develop antimetabolite-based consolidation regimens that minimize acute and long-term toxicities and improve the survival rate of children with standard-risk B-lineage acute lymphocytic leukemia (ALL). PATIENTS AND METHODS: Seven hundred twenty-seven eligible patients with standard-risk early pre-B ALL were registered onto the study. Seven hundred sixteen patients attained a complete remission (CR) after induction therapy. Of these, 114 patients were randomized to a different regimen and were the subject of a separate report. Six hundred two patients were randomized to receive one the following regimens: intermediate-dose methotrexate (IDMTX) with leucovorin rescue on weeks 7, 10, 13, 16, 19, and 22 (regimen A); regimen A plus asparaginase (ASP) administered intramuscularly (i.m.) weekly for 24 weeks (regimen B); or regimen A plus a 24-hour infusion of cytarabine (AraC) with each IDMTX (regimen C). After consolidation, patients were placed on maintenance therapy through week 156. Regimens A and C were opened in February 1986, and regimen B in May 1987. Comparisons are based on concurrently randomized patients (May 1987 to January 1991 between regimens A and B, and February 1986 to January 1991 between regimens A and C). RESULTS: The 5-year continuous CR (CCR) rates were not significantly different: A versus B, 78.1% (3.9 +/- SE) versus 83.3% +/- 3.5% and A versus C, 79.4% +/- 3.2% versus 83.5% +/- 2.9%; P by one-sided log-rank tests were .27 and .34, respectively. Significant treatment differences were not found with regard to sex, rate of testicular and CNS relapse, or CNS complications. During consolidation, regimen C had significantly more bacterial infections (P = .0032) and days spent in the hospital (P < .001) compared with regimen A. CONCLUSION: We were unable to show a statistical advantage of adding either ASP or AraC to IDMTX in terms of improvement in event-free survival (EFS).

Antimetabolites, Antineoplastic↗

PubMed1998

Prognostic significance of sex in childhood B-precursor acute lymphoblastic leukemia: a Pediatric Oncology Group Study.

PURPOSE: In childhood B-precursor acute lymphoblastic leukemia (ALL), possible interactions among sex, time, and widely used prognostic factors (age, WBC count, and DNA index) were investigated for the first 5 years after diagnosis. PATIENTS AND METHODS: All eligible patients aged 1 to less than 22 years, registered between February 1986 and September 1994 in two B-precursor ALL studies from the Pediatric Oncology Group (POG), were included in the analysis. Cutpoints for age (3.0, 5.0, and 10.0 years), WBC count (10, 50, and 100 x 10(9)/L), and DNA index (DI; 1.16) were defined. Four time periods after diagnosis (years 1, 2, 3, and 4 and 5 combined) were selected for the study of prognostic significance over time. The cut-off date for analysis was April 1996. RESULTS: A total of 3,717 children (2,010 boys and 1,707 girls) were included in the outcome analysis. No major differences between the sexes were observed in age, duration of symptoms before registration, WBC count, hemoglobin level, platelet count, ploidy, presence of CNS disease at diagnosis, or induction failure rate. Event-free survival (EFS) differences between sexes became significantly different from 2 years following diagnosis. At 5 years, in all subsets analyzed, boys fared worse than girls, although not all differences were statistically significant. Major sex differences in EFS were observed in older children (10 to 22 years), in patients with intermediate WBC counts (10 to 50 x 10(9)/ L), and in children who fit both of these subgroups, in whom the 2-year EFS was almost 20% higher in girls than in boys, reaching a 38% difference at 5 years. CONCLUSION: This study shows an outcome interaction among sex, time, and commonly used prognostic variables. The important sex difference observed at 2 and 5 years suggests that more intensive consolidation and/or maintenance therapy in some boys with B-precursor ALL should be investigated.

Adolescent↗

PubMed1998

Accumulation of methotrexate polyglutamates, ploidy and trisomies of both chromosomes 4 and 10 in lymphoblasts from children with B-progenitor cell acute lymphoblastic leukemia: a Pediatric Oncology Group Study.

Levels of accumulation of methotrexate polyglutamates were measured in vitro in lymphoblasts obtained at diagnosis from children with B-progenitor cell acute lymphoblastic leukemia (pro-B ALL). They were compared to numerical and structural chromosomal abnormalities present in these leukemic cells. In a series of 95 patients, the percent with high lymphoblast methotrexate polyglutamate levels increased with the increase in modal number of total chromosomes (p<0.001). Thus, lymphoblast methotrexate polyglutamate accumulation appeared to be closely linked to the extent of hyperdiploidy in childhood pro-B ALL. Lymphoblasts from 35 (88%) of the 40 children with hyperdiploid (>50 chromosomes) and 23 (88%) of 26 with hyperdiploid (DNA Index >1.16) pro-B ALL accumulated high levels of methotrexate polyglutamate, suggesting that they were more sensitive to methotrexate cytotoxicity. While children with hyperdiploid (DNA Index >1.16) pro-B ALL have a good prognosis, those with trisomies of both chromosomes 4 and 10, almost all of whom are hyperdiploid, have an even better outcome. There was no significant difference in methotrexate polyglutamate levels in lymphoblasts from 19 children with and 21 without trisomies of both chromosomes 4 and 10 (p = 0.25). The improved response to multi-agent chemotherapy conferred by the presence of trisomies of both chromosomes 4 and 10 in such patients may be due to increased sensitivity of their lymphoblasts to one or more anti-leukemic agents in addition to methotrexate.

Adolescent↗

PubMed1998

Myeloperoxidase gene expression in infant leukemia: a Pediatric Oncology Group Study.

A high incidence of co-expression of myeloid-associated antigens in infant B-precursor Acute Lymphocytic Leukemia (B-ALL) has been reported, but the significance of this finding is uncertain. To further assess myeloid differentiation and its prognostic significance in this disease, we investigated the frequency of myeloperoxidase (MPO) gene expression in the blast cells from 43 infants with B-ALL registered in a Pediatric Oncology Group (POG) Pilot Study for Treatment of Infant ALL, utilizing a molecular probe for detection of MPO messenger RNA (mRNA) by Northern blot hybridization and a monoclonal antibody to detect MPO-protein by immunohistochemical staining. Sufficient RNA for Northern blot was extracted from 32 bone marrow or blood samples. In two cases, MPO mRNA was determined by a reverse transcriptase-polymerase chain reaction assay and was negative in both cases. MPO-specific transcripts (MPO+) were present in 19 of 34 (56%) samples analyzed. Immunoreactive MPO protein was positive in 13 of the 20 (65%) patients studied. No correlation was found between MPO gene expression and clinical or laboratory features, karyotypic patterns or clinical outcome. The high frequency of MPO gene expression demonstrated in this study suggests that leukemogenic events in many cases of infant B-ALL appear to involve a pluripotent stem cell not yet fully committed to lymphoid differentiation.

Antibodies, Monoclonal↗

PubMed1998

Translocations involving chromosome 12p11-13, methotrexate metabolism, and outcome in childhood B-progenitor cell acute lymphoblastic leukemia: a Pediatric Oncology Group study.

Children with B-progenitor cell acute lymphoblastic leukemia whose lymphoblasts at diagnosis accumulate high levels of methotrexate (MTX) and MTX polyglutamates (MTXPGs) appear to have a good prognosis. This has been attributed to increased sensitivity of their blast cells to MTX. However, the proportion of children who are cured of B-progenitor cell acute lymphoblastic leukemia exceeds the number whose lymphoblasts accumulate high MTXPG levels. We report that lymphoblasts from patients with < 50 chromosomes who have translocations that involve the short arm of chromosome 12 accumulate low levels of MTXPGs. These patients appear to have an excellent survival because none of 14 patients with translocations affecting 12p has relapsed, 26-79 months following diagnosis.

Antimetabolites, Antineoplastic↗

PubMed1997

Treatment of children and young adults with early-stage non-Hodgkin's lymphoma.

BACKGROUND: Children and young adults with early-stage non-Hodgkin's lymphoma have an excellent prognosis, but treatment is prolonged and is associated with many side effects. We performed two studies to determine whether therapy could be simplified. METHODS: Between 1983 and 1991, we conducted two consecutive trials in children and young adults (age, <21 years) with early-stage non-Hodgkin's lymphoma. In the first trial, patients were treated for 9 weeks with induction chemotherapy consisting of vincristine, doxorubicin, cyclophosphamide, and prednisone, followed by 24 weeks of continuation chemotherapy with mercaptopurine and methotrexate. Half the patients were randomly assigned to receive involved-field irradiation. In the second trial, after the 9 weeks of induction chemotherapy, the patients were randomly assigned to receive 24 weeks of continuation chemotherapy or no further therapy. RESULTS: A total of 340 patients were enrolled in the two trials, 12 of whom did not have complete remissions. One hundred thirteen patients received nine weeks of chemotherapy without radiotherapy, 131 received eight months of chemotherapy without radiotherapy, and 67 received eight months of chemotherapy with radiotherapy. At five years, the projected rates of continuous complete remission were 89, 86, and 88 percent for the three groups, respectively. At five years, event-free survival among the patients with early-stage lymphoblastic lymphoma was inferior to that among the patients with other subtypes of lymphoma (63 percent vs. 88 percent, P<0.001). Continuation therapy was effective only in patients with lymphoblastic lymphoma. CONCLUSIONS: A nine-week chemotherapy regimen without irradiation of the primary sites of involvement is adequate therapy for most children and young adults with early-stage, nonlymphoblastic non-Hodgkin's lymphoma.

Adolescent↗

PubMed1997

Case-control study suggests a favorable impact of TEL rearrangement in patients with B-lineage acute lymphoblastic leukemia treated with antimetabolite-based therapy: a Pediatric Oncology Group study.

TEL gene rearrangement is the most common genetic lesion in pediatric acute lymphoblastic leukemia (ALL), occurring in about 25% of B-lineage cases. We previously showed that, among patients treated on St Jude protocols, TEL rearrangement independently conferred an excellent prognosis. To extend these results to patients treated with antimetabolite-based therapy, we performed Southern blot analysis to determine the TEL gene status of 104 cases of B-lineage ALL treated on Pediatric Oncology Group 8602, matched on age, gender, and leukocyte count. There were 52 failures among the 77 patients with germline TEL, compared with only 8 failures among 27 patients in the rearranged group. Based on a two-sided logistic regression analysis, stratified for age (subdivided at 10 years), leukocyte count (subdivided at 50,000), and gender, the estimated odds of failing by 4 years in the germline TEL group is 5.4 times that of the rearranged TEL group, with 95% confidence from 1.9 to 15.6, two-sided P = .0009. Thus, the presence of a rearranged TEL gene is also associated with an improved survival among patients treated with antimetabolite-based therapy. Our results indicate that all newly diagnosed ALL patients should be screened for TEL gene rearrangements and suggest that these patients are candidates for less intensive therapy.

Antimetabolites, Antineoplastic↗