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J Nachman

Publications and source records attributed to J Nachman.

At least 19 recordsLinked to original sources
PubMed2006

The Eighth International Childhood Acute Lymphoblastic Leukemia Workshop ('Ponte di legno meeting') report: Vienna, Austria, April 27-28, 2005.

The International Acute Lymphoblastic Leukemia Working Group, the so-called 'Ponte di Legno Workshop' has led to substantial progress in international collaboration in leukemia research. On April 27-28, 2005, the 8th Meeting was held in Vienna, Austria, to continue the discussions about special common treatment elements in randomized clinical trials, ethical and clinical aspects of therapy. Furthermore, collaborative projects of clinical relevance with special emphasis on rare genetic subtypes of Childhood ALL were established. The following report summarizes the achievements and aspects of possible future cooperation.

Austria↗
PubMed2005

The seventh international childhood acute lymphoblastic leukemia workshop report: Palermo, Italy, January 29--30, 2005.

Between 1995 and 2004, six International Childhood Acute Lymphoblastic Leukemia (ALL) Workshop have been held, and the completion of several collaborative projects has established the clinical relevance and treatment options for several specific genetic subtypes of ALL. This meeting report summarizes the data presented in the seventh meeting and the discussion.

Antineoplastic Agents↗
PubMed2002

Immunodominance and tumor escape.

Cancers in mouse and man express multiple tumor-specific as well as tumor-associated antigens. Immunodominance in the host response to these antigens can result in successive selection of heritable antigen loss variants. Immunodominance may also prevent the development of responses to new tumor-specific antigens that may arise during tumor progression. Some tumor-specific antigens are retained during tumor progression possibly because they are essential for survival of the malignant phenotype. Immunodominance may allow cancer cells to escape even after loss of a single MHC Class I allele because cross-presentation of the retained antigen by this allele that must be expressed on the surrounding antigen presenting cells sustains the immunodominant response. This prevents effective responses to secondary antigens that may remain as potential targets. Immunization with in vitro selected cancer cell variants that lack the immunodominant antigen can break the immunodominance and prevent escape of cancers from host immunity.

Alleles↗
PubMed2000

Immunological enhancement of primary tumor development and its prevention.

While it has been known for decades that the growth of tumor transplants can be enhanced immunologically, the potential significance of these previous findings to the development of primary tumors and the mechanisms of tumor enhancement has remained obscure. This review will summarize recent experiments indicating that primary tumor development can be enhanced by active immunization. The evidence suggests that antibodies, B cells and CD4+ T cells can play a critical role in enhancing the development of primary, tumors, whereas endogenous interferon-gamma (IFNgamma) can counteract enhancement. Thus, we envision two possible functions of IFNgamma: (i) preventing B cell and antibody enhancement and (ii) counteracting tumor promotion independent of T and B cells.

Animals↗
PubMed2000

Structural basis for specificity switching of the Src SH2 domain.

The Src SH2 domain binds pYEEI-containing phosphopeptides in an extended conformation with a hydrophobic pocket, which includes ThrEF1, binding Ile(pY +3). Mutating ThrEF1 to tryptophan switches specificity to an Asn(pY +2) requirement, yielding a biological mimic of the Grb2 SH2 domain. Here we show that the Src ThrEF1Trp SH2 domain mutant binds pYVNV phosphopeptides in a beta turn conformation, which, despite differing conformations of the interacting tryptophan, closely resembles the native Grb2/pYVNV cognate peptide binding mode. The ThrEF1Trp substitution therefore switches specificity by physically occluding the pTyr +3 binding pocket and by providing additional interaction surface area for Asn(pY +2). This demonstrates structurally how novel SH2 domain specificities may rapidly evolve through single amino acid substitutions and suggests how new signaling pathways may develop.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Radiation therapy for consolidation of metastatic or recurrent sarcomas in children treated with intensive chemotherapy and stem cell rescue. A feasibility study.

PURPOSE: To assess the role of consolidative radiation therapy (CRT) in conjunction with myeloablative therapy with or without total body irradiation (TBI) in children and young adults with metastatic or recurrent sarcoma. METHODS AND MATERIALS: Twenty-one pediatric sarcoma patients with metastatic (10) or recurrent (11) disease were entered on a prospective feasibility study of intensive myeloablative therapy with or without TBI. Median patient age was 17.8 years (range, 9.4-24.7 years). Primary histologies included Ewing's (12), PNET (3), and other soft tissue sarcomas (6). Twenty patients received induction chemotherapy. Myeloablative therapy consisted of TBI in 11 patients with either high dose melphalan/etoposide (9) or high dose cytoxan/thiotepa (2). TBI consisted of 12 Gy in 2 Gy fractions delivered twice daily over 3 days. Ten patients received high dose chemotherapy alone, either with thiotepa/carboplatinum/etoposide (8) or cytoxan/carboplatinum (2). Myeloablative therapy was followed by autologous stem cell rescue (ASCR) 24 to 48 hours after completing chemotherapy. Fourteen patients (67%) received CRT either prior to (5) or following (9) myeloablative therapy. Median CRT dose was 37.2 Gy (range, 20-60). Fifty-one disease sites were present prior to myeloablative therapy. Twelve (24%) were bulky (> 8 cm) and 18 (35%) underwent surgical debulking. The median follow-up of surviving patients was 15 months (range, 8-20) with 25% of patients having been followed for more than 20 months. RESULTS: The 3-year actuarial disease-free (DFS) and overall survival (OS) rates for the entire group were 36% and 27%, respectively. Following myeloablative treatment, responses were: 11 complete, 6 partial, 1 stable, and 3 progressive disease. Sixteen patients (71%) have relapsed. The most common site of relapse was the lung (13). Of the 51 disease sites present prior to myeloablative therapy, 36 sites (71%) were amenable to CRT. Nonamenable sites were: multiple lung metastases (13) and bone marrow (2). Twenty-six amenable sites (51%) received CRT either prior to (14) or following (12) ASCR. Amenable sites treated with CRT had a better 3-year actuarial local control (80 vs 37%) (p = 0.0065) than amenable sites not treated with CRT. Factors associated with improved disease-free survival (DFS) in univariate analysis were induction chemotherapy response (p = 0.002) and extent of surgical resection (p = 0.045). There was a trend toward improved DFS on univariate analysis with the use of TBI as part of myeloablative therapy (p = 0.07). The one factor associated with improved OS on univariate analysis was induction chemotherapy response (p = 0.007). Multivariate analysis revealed that induction chemotherapy response is the only factor that remains significant for DFS (p = 0.032) as well as for OS (p = 0.017). Patients with complete response to induction therapy had 40% probability of survival versus all other patients who had 10% survival (p = 0.05). CONCLUSION: Consolidative radiotherapy is feasible in primary metastatic or recurrent pediatric sarcoma patients treated with myeloablative therapy with or without TBI. CRT to sites amenable to irradiation provided an improved 3-year actuarial local control than that seen in sites amenable to CRT that did not undergo radiotherapy. There was a trend for improved DFS with the use of TBI. Improved DFS and OS can be predicted by response to induction therapy. This intensive regimen may improve the cure rate of advanced pediatric sarcomas in select patients.

Adolescent↗
PubMed1999

Expression of aberrantly spliced oncogenic ikaros isoforms in childhood acute lymphoblastic leukemia.

PURPOSE: We sought to determine if molecular abnormalities involving the Ikaros gene could contribute to the development of acute lymphoblastic leukemia (ALL) in children. PATIENTS AND METHODS: We studied Ikaros gene expression in normal human bone marrow, normal thymocytes, normal fetal liver-derived immature lymphocyte precursor cell lines, eight different ALL cell lines, and leukemic cells from 69 children with ALL (T-lineage ALL, n = 18; B-lineage ALL, n = 51). Expression of Ikaros protein and its subcellular localization were examined by immunoblotting and confocal laser-scanning microscopy, respectively. Polymerase chain reaction (PCR) and nucleotide sequencing were used to identify the specific Ikaros isoforms expressed in these cells. Genomic sequencing of splice junction regions of the Ikaros gene was performed in search for mutations. RESULTS: In each of the ALL cases, we found high-level expression of a non-DNA-binding or aberrant DNA-binding isoform of Ikaros with abnormal subcellular compartmentalization patterns. In contrast, only wild-type Ik-1 and Ik-2 isoforms with normal subcellular localization were found in normal bone marrow cells and thymus-derived or fetal liver-derived normal lymphocyte precursors. In leukemic cells expressing the aberrant Ikaros coding sequences with the 30-base-pair deletion, genomic sequence analysis of the intron-exon junctions between exons 6 and 7 yielded the wild-type sequence. We identified a single nucleotide polymorphism (SNP) affecting the third base of the triplet codon for a proline (CCC or CCA) in the highly conserved bipartite activation region (viz, A or C at position 1002 numbering from the translation start site of Ik-1) within our Ikaros clones. Bi-allelic expression of truncated and/or non-DNA-binding isoforms along with wild-type isoforms was observed in leukemic cells, which implicates trans-acting factor(s) affecting splice site recognition. CONCLUSION: Our findings link specific molecular defects involving the Ikaros gene to childhood ALL. Posttranscriptional regulation of alternative splicing of Ikaros RNA seems to be defective in leukemic lymphocyte precursors from most children with ALL. Consequently, leukemic cells from ALL patients, in contrast to normal lymphocyte precursors, express high levels of non-DNA-binding Ikaros isoforms that are reminiscent of the non-DNA-binding Ikaros isoforms that lead to lymphoblastic leukemia in mice.

Adolescent↗
PubMed1999

Prognostic significance of T-lineage leukemic cell growth in SCID mice: a Children's Cancer Group study.

Contemporary intensive therapies are effective for the majority of pediatric T-lineage acute lymphoblastic leukemia (ALL) patients, thus current challenge is to identify patients who may benefit from alternative treatment modalities. Previously, we demonstrated that human leukemic cell growth in the severe combined immunodeficiency (SCID) mouse was a significant prognostic factor for very high risk B-lineage ALL patients. In the current report we show that primary leukemic cells from 24 of 88 (27%) T-lineage ALL patients (SCID+) caused histopathologically detectable leukemia in SCID mice. These SCID+ patients were similar to SCID- (n = 64) patients with respect to virtually all presenting features, including age, sex, race, and leukocyte count. Growth of primary leukemic cells in SCID mice was not a significant predictor of outcome for the aggregate population of T-lineage ALL patients. Two-year event-free survival (EFS) outcomes for SCID+ patient and SCID- patients were 76.2% (SD = 5.6%) and a 64.0% (SD = 10.4%; p = 0.20). Overall survival also was similar between the two groups (p = 0.36). Among the subset of patients with M1 or M2 marrow status by day 7 of induction chemotherapy (rapid early responders), those who were SCID+ had poorer outcomes than those who were SCID-, with a 2-year EFS of 68.4% (SD = 11.9%) vs. 85.7% (SD = 6.0%) and relative hazard rate of 3.06 (p = 0.06). These data suggest that leukemic cell growth in SCID mice may identify a subset of T-lineage ALL patients who are at higher risk for relapse despite achieving a rapid early response to induction chemotherapy.

Animals↗
PubMed1999

Expression of dominant-negative Ikaros isoforms in T-cell acute lymphoblastic leukemia.

Ikaros, a zinc finger-containing DNA-binding protein, is required for normal lymphocyte development. Germ-line mutant mice that express only non-DNA binding dominant-negative "leukemogenic" Ikaros isoforms lacking critical NH2-terminal zinc fingers develop an aggressive form of T-cell leukemia. We studied Ikaros gene expression in leukemic cells from 18 children with T-cell acute lymphoblastic leukemia (T-ALL). In each of the 18 T-ALL cases as well as JK-E6-1 and MOLT-3 cell lines, we found high-level expression of dominant-negative isoforms of Ikaros with abnormal subcellular compartmentalization patterns. Nuclear extracts from these cells failed to bind to the IKAROS-specific binding sequence in DNA. PCR cloning and sequencing confirmed that JK-E6-1 and MOLT-3 cell lines as well as leukemic cells from 9 of 10 patients with T-ALL expressed dominant-negative Ikaros isoforms Ik-4, Ik-7, and Ik-8 that lack critical NH2-terminal zinc fingers. In 6 of 10 patients, we detected a specific mutation leading to an in-frame deletion of 10 amino acids (delta KSSMPQKFLG) upstream to the transcription activation domain and adjacent to the COOH-terminal zinc fingers of Ik-2, Ik-4, Ik-7, and Ik-8. Thus, children with T-ALL express high levels of dysfunctional dominant-negative Ikaros isoforms.

Adult↗
PubMed1998

High-energy total body irradiation as preparation for bone marrow transplantation in leukemia patients: treatment technique and related complications.

PURPOSE: Bone marrow transplantation with conditioning regimens that include total-body irradiation (TBI) is widely used in patients with acute lymphoblastic and acute myelocytic leukemias. The major causes of death in this population are relapse of leukemia, infection, and treatment related complications. Our purpose was to achieve a homogenous radiation dose distribution and to minimize the dose to the lungs, liver, and kidneys so that the incidence of organ injury was reduced. METHODS AND MATERIALS: Dose to the bone marrow, midplane, and periphery was quantified by use of thermoluminescent detectors in a bone-equivalent tissue phantom. In an effort to reduce the risk of complications, we treated relapsed or refractory leukemia patients with TBI administered in fractionated, parallel opposed large fields with 24 MV photons, using tissue compensation and partial-transmission lung shielding. Tissue toxicities were then determined. RESULTS: Dose quantitation in bone-equivalent and tissue-equivalent phantoms demonstrated that backscatter and pair production interactions adjacent to bone increased the bone marrow dose by 6 to 11%. At an SSD of 400 cm and at patient diameters of 20 to 40 cm, the percent inhomogeneity across the phantom with 24 MV photons was 0 to 0.3%, compared to 4 to 6% for 6 MV photons. End-organ toxicities consisted of clinical interstitial pneumonitis in six patients, idiopathic interstitial pneumonitis in three patients, renal toxicity in seven patients, and veno-occlusive disease of the liver in one patient. Toxicities did not correlate with fractionation schedule. CONCLUSIONS: Total-body irradiation administered with 24 MV photons increases the dose deposition in bone marrow through pair production and backscatter interactions occurring in bone. Because percent depth dose increases with SSD, the 24 MV beam is more penetrating at a 400 cm distance than at 100 cm and dose homogeneity is improved with higher energies. Thus, the incidence of radiation-mediated injury to lung, liver, and kidney is reduced. This is an effective preparatory regimen for patients with high-risk leukemias requiring bone marrow transplantation.

Adolescent↗
PubMed1998

MOPP or radiation in addition to ABVD in the treatment of pathologically staged advanced Hodgkin's disease in children: results of the Children's Cancer Group Phase III Trial.

PURPOSE: A randomized trial designed to compare mechlorethamine, vincristine, procarbazine, and prednisone (MOPP)/doxorubicin, bleomycin, vinblastine, and daccarbazine (ABVD) (regimen A) with ABVD plus low-dose regional (extended-field) radiation therapy (EF RT) (regimen B) for the treatment of children and adolescents with stages III and IV Hodgkin's disease was conducted by the Children's Cancer Group (CCG-521) from 1986 until 1990. PATIENTS AND METHODS: One hundred eleven eligible patients were randomized, 57 to regimen A and 54 to regimen B. All patients had pathologically verified stage III or stage IV Hodgkin's disease. RESULTS: Overall survival (S) is 87% at 4 years and event-free survival (EFS) is 82%. Patients randomized to ABVD plus EF RT have a 4-year EFS of 87% compared with 77% for patients randomized to MOPP/ABVD (P = .09, two-sided). Patients randomized to ABVD plus EF RT have a 4-year S of 90% compared with 84% for patients randomized to MOPP/ABVD (P = .45, two-sided). Significant prognostic factors in multivariate analysis for EFS are stage of disease, erythrocyte sedimentation rate (ESR) at diagnosis, liver size at diagnosis, and, among stage III patients, the size of the mediastinal mass at diagnosis. The acute toxicities of treatment are largely hematopoietic in nature, whereas acute pulmonary and cardiac toxicities are modest and not limiting. CONCLUSION: The results of this study show that, in advanced-stage Hodgkin's disease in children, equivalent results can be obtained by the addition of either MOPP or low-dose EF RT to the ABVD regimen; whether the addition of either contributes to outcome was not addressed in this study and will require additional testing. It is clear, however, that MOPP chemotherapy can safely be eliminated from front-line combination chemotherapy regimens for advanced Hodgkin's disease in pediatric patients.

Adolescent↗
PubMed1998

Response of children with high-risk acute lymphoblastic leukemia treated with and without cranial irradiation: a report from the Children's Cancer Group.

PURPOSE: Intensified intrathecal (i.t.) chemotherapy without cranial radiation therapy (CRT) prevents CNS relapse in children with low-risk and intermediate-risk acute lymphoblastic leukemia (ALL). In the current study, high-risk ALL patients who achieved a rapid early response (RER) to induction chemotherapy were randomized to receive intensive systemic chemotherapy and presymptomatic CNS therapy that consisted of either i.t. methotrexate (MTX) and CRT or intensified i.t. MTX alone. PATIENTS AND METHODS: Children (n = 636) with high-risk ALL (aged 1 to 9 years and WBC count > or = 50,000/microL or age > or = 10 years, excluding those with lymphomatous features) who achieved an RER (< or = 25% marrow blasts on day 7) to induction therapy and lacked CNS disease at diagnosis were randomized to receive systemic therapy with either i.t. MTX and CRT (regimen A, n = 317) or intensified i.t. MTX alone (regimen B, n = 319). RESULTS: Interim analysis in July 1993 revealed 3-year event-free survival (EFS) estimates of 82.1% +/- 4.0% (SD)and 70.4% +/- 4.2% for patients treated on regimens A and B, respectively (P = .004). As of January 1996, outcome had changed: 5-year EFS estimates were 69.1% +/- 3.4% and 75.0% +/- 2.7% for regimens A and B, respectively (P = 0.50). Marrow relapses comprised 57 events on regimen A and 43 events on regimen B. Fewer late events occurred on regimen B. CONCLUSION: For high-risk pediatric ALL patients who show an RER to induction therapy and are treated with systemic Children's Cancer Group (CCG)-modified Berlin-Frankfurt-Munster (BFM) chemotherapy, presymptomatic CNS therapy that consists of either i.t. MTX plus CRT or intensified i.t. MTX alone results in a similar 5-year EFS outcome. Furthermore, intensified i.t. MTX may protect against late bone marrow relapse.

Adolescent↗
PubMed1998

Prognostic significance of B-lineage leukemic cell growth in SCID mice: a Children's Cancer Group Study.

Primary leukemic cells isolated from children (N = 681 ) with newly diagnosed B-lineage ALL enrolled on risk-adjusted treatment protocols of the Children's Cancer Group (CCG) were injected via the tail vein into 7-10 week old SCID mice. Leukemic cells from 104 of 681 patients (15.3%) were able to engraft and proliferate in one or more SCID mouse organs. These SCID+ patients were somewhat more likely than SCID patients to be older than 10 years of age (p = 0.03) and have WBC counts >20,000/microL (p = 0.04), but the groups were similar with respect to all other presenting features. Event-free survival (EFS) outcome at 3 years of follow-up was similar for SCID+ patients compared with SCID- patients (79.2%, SD = 5. 1% vs. 84.8%, SD = 2.8%; p = 0.20). Overall survival also was similar between the two groups (p = 0.93). This result was maintained within the subgroups of lower risk (N = 448) and higher risk (N = 233) patients. However, there were trends for poorer outcome among patients whose cells caused overt leukemia in SCID mice and infiltrated either 6 or more organs (p = 0.03), skeletal muscle (p = 0.0003), kidney (p = 0.05), or spleen (p = 0.06). Thus, engraftment of primary leukemic cells in SCID mice was not a significant predictor of outcome for the aggregate population of B-lineage ALL patients, the majority of whom were low risk, treated according to contemporary intensive chemotherapy programs of the CCG. However, development of disseminated overt leukemia and infiltration of SCID mouse skeletal muscle by primary leukemic cells from adjacent bone marrow may reflect a biologically more aggressive disease and identify patients at higher risk for treatment failure.

Adolescent↗
PubMed1997

Clinical features and treatment outcome of children with myeloid antigen positive acute lymphoblastic leukemia: a report from the Children's Cancer Group.

Leukemic cells from a significant number of children with acute lymphoblastic leukemia (ALL) express protein antigens characteristic of both lymphoid and myeloid cells, yet the clinical significance of this immunophenotype has remained controversial. In the current study, we have determined relationships between myeloid antigen expression and treatment outcome in a large cohort of children with newly diagnosed ALL. A total of 1,557 children enrolled on risk-adjusted Children's Cancer Group studies were classified as myeloid antigen positive (My+) or myeloid antigen negative (My-) B-lineage ALL (BL) or T-lineage ALL (TL), according to expression of CD7, CD19, CD13, and CD33 antigens on the surface of their leukemic cells. My+ patients in both BL and TL groups were more likely than My- patients to have favorable presenting features. Induction therapy outcome was similar for My+ and My- patients in both the BL and TL categories. Importantly, 4-year event-free survival (EFS) was similar for My+ BL (77.0%, standard deviation [SD] = 4.0%) versus My- BL (75.9%, SD = 1.8%) and for My+ TL (72.7%, SD = 7.1%) versus My- TL (70.1%, SD = 5.7%). An overall relative hazard rate (RHR) of 0.89 (P = .49) was determined by a cross strata analysis for My+ versus My- patients. Moreover, similar EFS and RHR also were found when My+ and My- BL patients were compared according to National Cancer Institute risk classification. Thus, patients with My+ ALL have similar treatment outcomes as My- ALL patients. In contrast to previous studies, this result was independent of treatment risk category, demonstrating that myeloid antigen expression was not an adverse prognostic factor for childhood ALL.

Adolescent↗
PubMed1997

Cellular expression of antiapoptotic BCL-2 oncoprotein in newly diagnosed childhood acute lymphoblastic leukemia: a Children's Cancer Group Study.

We found a marked variation in BCL-2 oncoprotein expression levels of primary leukemic cells from 338 children with newly diagnosed acute lymphoblastic leukemia (ALL). None of the high-risk features predictive of poor treatment outcome in childhood ALL, such as older age, high white blood cell (WBC) count, organomegaly, T-lineage immunophenotype, ability of leukemic cells to cause overt leukemia in severe combined immunodeficient (SCID) mice, presence of MLL-AF4, and BCR-ABL fusion transcripts were associated with high levels of BCL-2 expression. Overall, high BCL-2 levels were not associated with slow early response, failure to achieve complete remission, or poor event-free survival. High BCL-2 levels in primary leukemic cells predicted slow early response only in T-lineage ALL patients, which comprised approximately 15% of the total patient population. Even for this small subset of patients, the level of BCL-2 expression did not have a significant impact on the short-term event-free survival.

Adolescent↗
PubMed1997

Clinical features and treatment outcome of children with biphenotypic CD2+ CD19+ acute lymphoblastic leukemia: a Children's Cancer Group study.

Leukemic cells from a subset of children with acute lymphoblastic leukemia (ALL) express lymphoid antigens of both T lineage and B lineage, but the clinical significance of this immunophenotype is unknown. We now report the first comprehensive comparison of treatment outcomes among a large cohort of children with CD2+ CD19+ biphenotypic ALL (N = 77), B-lineage ALL (BL) (N = 1,631), or T-lineage ALL (TL) (N = 347) ALL who were treated on risk-adjusted Children's Cancer Group (CCG) protocols. CD2+ CD19+ patients were more similar to BL than TL patients with respect to presenting features and antigen expression. The percentages of patients achieving successful induction therapy outcome were 98.7%, 97.8%, and 97.3% for CD2+ CD19+, BL, and TL patients, respectively. Univariate comparisons of 4-year event-free survival (83.7%, 72.8%, 75.2% for CD2+ CD19+, BL, and TL patients, respectively) achieved borderline significance (CD2+ CD19+ B, P = .08; CD2+ CD19+ v T, P = .07). Relative hazard rate (RHR) estimates for BL and TL compared with CD2+ CD19+ were 1.79 and 1.90, respectively, implying a better outcome for biphenotypic patients. However, multivariate adjusted RHRs for BL and TL compared with CD2+ CD19+ were 1.43 (P = .29) and 1.16 (P = .76), respectively, suggesting a significant reduction in risk for BL or TL patients once adjustment was made for the more favorable characteristics of the CD2+ CD19+ group. Thus, pediatric ALL patients treated on contemporary CCG protocols who present with CD2+ CD19+ biphenotypic leukemia generally have good treatment outcomes, due in part to their favorable presenting features.

Adolescent↗