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Biomedical subjects

M P Link

Publications and source records attributed to M P Link.

At least 55 records · Page 3Linked to original sources
PubMed1993

Clinical features and outcome of T-cell acute lymphoblastic leukemia in childhood with respect to alterations at the TAL1 locus: a Pediatric Oncology Group study.

Alteration of the TAL1 locus is the most common nonrandom genetic defect in childhood T-cell acute lymphoblastic leukemia (T-ALL). To determine if rearrangements of the TAL1 proto-oncogene confer a distinct leukemic phenotype, we studied leukemic peripheral blood or bone marrow samples from 182 children with newly diagnosed T-ALL enrolled on Pediatric Oncology Group treatment protocols. Forty-eight (26%) of the samples had a local rearrangement of the TAL1 locus. Demographic and clinical features were compared for patient subgroups with and without TAL1 rearrangements. The only clinical correlates that were significantly associated with TAL1 gene rearrangements were higher white blood cell count (P = .017) and higher hemoglobin (P = .007) at diagnosis. Immunophenotypically, samples with altered TAL1 were more likely to be CD2+ (P = .001) and lack CD10 (cALLa) expression (P = .007) than those without the rearrangement. There was a trend toward improved event-free survival (EFS) in patients with TAL1 rearrangements (4-year EFS was 44% +/- 7% for patients without the rearrangements v 59% +/- 11% for those with rearrangements), but the difference was not significant (P = .34). The role of TAL1 in leukemogenesis has yet to be clearly defined, and the prognostic significance of TAL1 gene rearrangements in T-ALL deserves further study.

Adolescent↗
PubMed1993

Detection of the (11;22)(q24;q12) translocation of Ewing's sarcoma and peripheral neuroectodermal tumor by reverse transcription polymerase chain reaction.

Ewing's sarcoma and the related primitive neuroectodermal tumor (PNET) share a unique and specific t(11;22)(q24;q12) chromosomal translocation. The breakpoints have recently been cloned and shown to involve the EWS gene on chromosome 22 and the FLI-1 gene on chromosome 11. Translocation results in the fusion of these genes on the der(22) chromosome, resulting in the production of a novel chimeric EWS/FLI-1 message. Using oligonucleotide primers derived from EWS and FLI-1 complementary DNAs, we were able to amplify a specific fusion transcript from 18 of 18 cases containing t(11;22) and 10 of 14 cases of Ewing's sarcoma/PNET that had unsuccessful cytogenetics. No EWS/FLI-1 fusion transcripts were detected in five cell lines derived from cases of pediatric sarcomas having a histological diagnosis other than Ewing's sarcoma/PNET. The sensitivity and specificity of this PCR analysis demonstrates the usefulness of this approach for the primary diagnosis of t(11;22)-containing Ewing's sarcoma/PNET and for the detection of metastatic or residual disease.

Amino Acid Sequence↗
PubMed1992

Isochromosomes in childhood acute lymphoblastic leukemia: a collaborative study of 83 cases.

Cytogenetic analysis of leukemic cells from 2,805 children with newly diagnosed acute lymphoblastic leukemia (ALL) identified 83 cases (3%) that had a stemline with at least one isochromosome. The i(9q) was present in 28 (1%), the i(17q) in 23 (0.8%), and the i(7q) in 23 (0.8%). Other isochromosomes--i(21q), i(6p), i(1q), i(8q), or i(Xq)--were found in only 12 cases (0.4%). The isochromosome cases were more likely than were other ALL cases to have a pre-B immunophenotype (38% v 25%, P = .02) and leukemic cell hyperdiploidy greater than 50 (37% v 24%, P = .02); five cases had both features. The i(9q) was associated with age greater than 10 years (P less than .05) and the pre-B immunophenotype (P = .05); both the i(17q) and i(7q) had high frequencies of hyperdiploidy greater than 50 (P less than .0001 and P = .05, respectively). The t(1;19)(q23;p13) was a common feature (23%) in cases with the i(9q), i(7q), i(6p), or i(1q). These findings establish the i(9q), i(17q), and i(7q) as nonrandom chromosomal abnormalities in ALL. The prognostic significance of the presence of isochromosome(s) remains to be determined.

Adolescent↗
PubMed1992

t(2;14)(p13;q32): a recurring abnormality in lymphocytic leukemia. A Pediatric Oncology Group study.

Chromosome banding studies of 1,411 children with newly diagnosed acute lymphocytic leukemia (ALL) identified two patients with the t(2;14)(p13;q32) chromosome abnormality and a third patient with a complex three-way translocation involving the same breakpoints on chromosomes 2 and 14 but also involving chromosome 12 at band q11. The three cases demonstrated variability of immunophenotypes: one was a T-cell ALL, and two were early pre-B ALLs. All three patients achieved complete remissions and have remained in remission for 14-19 months.

B-Lymphocytes↗
PubMed1992

Acute lymphoblastic leukemia occurring as a second malignant neoplasm in childhood: report of three cases and review of the literature.

PURPOSE: The long-term effects of childhood cancer and its therapy are a problem of increasing concern. One of the most important of these late effects is the development of second malignant neoplasms (SMNs), which occur in approximately 8% of children within 20 years of diagnosis of a malignancy. These secondary cancers may result (individually or in combination) from increased genetic susceptibility, the mutagenic effects of chemotherapy and/or radiation therapy, or chance. Whereas the development of acute nonlymphocytic leukemia (ANLL) as an SMN is a well-recognized phenomenon, acute lymphoblastic leukemia (ALL) has been infrequently described as an SMN in either adults or children. PATIENTS AND METHODS: We report three patients treated at our institution in whom ALL developed as an SMN after treatment for neuroblastoma, Wilms' tumor, and Hodgkin's disease. These cases prompted us to review the published literature for cases of secondary ALL in childhood. Patients whose initial malignancy was diagnosed at age less than 16 years were classified as pediatric patients. SMNs were defined as cancers of clearly distinct histologic type occurring 6 or more months after diagnosis of the first malignant neoplasm. RESULTS: Including the three index cases, a total of 18 children with secondary ALL are reviewed, and the clinical features are discussed and compared with those of secondary ANLL. CONCLUSIONS: This review summarizes the published case histories of secondary ALL. The data suggest that ALL represents approximately 5% to 10% of the cases of acute leukemia that arise as SMNs in both adults and children.

Adolescent↗
PubMed1992

Intensive sequential chemotherapy for children with acute myelogenous leukemia: VAPA, 80-035, and HI-C-Daze.

Between 1976 and 1988 we treated 228 children age 18 years or less with AML on three consecutive protocols: Vapa, 80-035 and Hi-C Daze. All three protocols used intensive consolidation chemotherapy. VAPA and 80-035 used an anthracycline with standard dose cytosine arabinoside (ara-c) for remission induction followed by twelve to fourteen months of intensive sequential chemotherapy. Results were similar for these two treatment protocols. 90/125 (72%) of the patients achieved a complete remission with 45% projected disease free survival for the complete responders, and an event free survival of 31%. 8/26 (VAPA) and 3/21 (80-035) relapses were primary CNS. No factor significantly influenced the rate of complete remission, but M4 and M5 FAB subtypes and WBC greater than 100,000/ul predicted for shorter remission duration. 103 children received Hi-C DAZE. The protocol differed by utilizing high-dose ara-c during induction and consolidation and pairing VP-16 with azacytidine. Hi-C DAZE was modified after the first 33 patients (group 1) because of CNS toxicity; VP-16/azacytidine were substituted for high dose ara-c/daunorubicin as the second induction course for the next 70 patients (group 2). Twenty eight of 33 (85%) of group 1 and 54/70 (77%) of group 2 entered remission.

Adolescent↗
PubMed1992

Childhood malignant non-Hodgkin lymphomas of uncommon histology.

Uncommon histologies were identified in 36 of 1336 cases (2.7%) of newly diagnosed childhood non-Hodgkin lymphoma (NHL). Seventeen cases were classified as follicular (six cases as mixed small and large cell, nine as large cell, and two as small non-cleaved cell) and 19 cases as diffuse (18 cases as mixed small and large cell, and one as small cell lymphocytic). The follicular pattern group included a preponderance of male patients; the median age at diagnosis was 11.7 years. These children presented primarily with low-stage disease involving lymph nodes or tonsils. All patients except one achieved complete remission and remain disease-free for 11 months to 18.8 years (actuarial 5-year event-free survival, 94%). The group with diffuse histologies was similar in sex ratio, age at diagnosis (median = 12.1 years), and nodal involvement, but tended to have more advanced-stage disease. Moreover, only 14 of 19 (74%) children with diffuse intermediate-grade histologies are alive in continuous complete remission (actuarial 5-year event-free survival, 70%). These results suggest that follicular pattern childhood NHL has an excellent prognosis, whereas cases with diffuse intermediate-grade histology are prognostically similar to those with diffuse high-grade histologies.

Adolescent↗
PubMed1991

The t(1;19)(q23;p13) results in consistent fusion of E2A and PBX1 coding sequences in acute lymphoblastic leukemias.

The t(1;19)(q23;p13) chromosomal translocation is observed cytogenetically in 25% of children with pre-B-cell acute lymphoblastic leukemia (ALL) and is associated with an adverse treatment outcome. The t(1;19) juxtaposes the E2A gene from chromosome 19 with the PBX1 gene on chromosome 1, leading to the production of fusion transcripts and resultant chimeric proteins that contain the transcriptional-activating motif of E2A and the DNA-binding homeodomain of PBX1. To investigate the molecular nature of E2A/PBX1 fusion in patients with t(1;19) ALL we used an RNA-based polymerase chain reaction (PCR) procedure to amplify a portion of the chimeric transcript. We detected E2A/PBX1 fusion transcripts in cells from 97% (37 of 38) of cases in which the t(1;19) had been observed cytogenetically. Molecular evidence of E2A/PBX1 fusion transcripts was also observed in a patient in whom a t(1;19) was not detected cytogenetically and in one patient with subclinical levels of minimal residual disease before overt clinical relapse. In all PCR-positive cases the junction of E2A and PBX1 coding sequences occurred at precisely the same location as demonstrated by hybridization of PCR products with a fusion site-specific detection oligonucleotide. These findings demonstrate the consistent fusion of E2A and PBX1 coding sequences resulting from t(1;19) and suggest that site-specific fusion of E2A and PBX1 is an important pathogenic event in t(1;19) ALL.

Base Sequence↗
PubMed1991

Consistent involvement of the bcr gene by 9;22 breakpoints in pediatric acute leukemias.

To investigate the relationship of bcr-abl fusion mRNAs with childhood acute lymphoblastic leukemias (ALL), we examined 27 pediatric Philadelphia chromosome (Ph1)-positive acute leukemias using a reverse polymerase chain reaction (PCR) procedure. In cells from 24 leukemias, single bcr-abl PCR products were detected that corresponded to breakpoints in the minor breakpoint cluster region (mbcr in intron 1 of the bcr gene) associated with production of the P190 fusion protein. Cells from the three remaining leukemias contained breakpoints in the major breakpoint cluster region (Mbcr) as shown by PCR and Southern blot analyses. These three leukemias also contained low levels of the mbcr PCR product that may have resulted from alternative splicing of the bcr-abl precursor RNA. A screen of 35 additional leukemias from patients who failed therapy before day 180 (induction failures or early relapses) found one case with unsuccessful cytogenetics to express Mbcr-abl RNA. All four children with Mbcr breakpoints had white blood cell levels in excess of 250,000 at presentation (compared with 2 of 24 with mbcr breakpoints) and two had hematologic and clinical features suggestive of chronic myelogenous leukemias (CML) in lymphoid blast crisis. Our results indicate that in Ph1-positive pediatric leukemias, all 9;22 breakpoints occur in one of the two known breakpoint cluster regions in the bcr gene on chromosome 22. The reverse PCR reliably detected all patients with cytogenetic t(9;22) and is capable of detecting additional Ph1-positive leukemias that are missed by standard cytogenetics. Furthermore, the Mbcr-type breakpoint, associated with production of p210, can be seen in childhood leukemias presenting either as clinical ALL or as apparent lymphoid blast crisis of CML, suggesting that t(9;22) breakpoint locations do not exclusively determine the biologic and clinical features of pediatric Ph1-positive ALL.

Adolescent↗
PubMed1991

Hodgkin's disease. Treatment of the young child.

Age of a patient when afflicted with Hodgkin's disease is an important prognostic factor. Although there are histologic and stage differences as a function of age, the younger a patient is when diagnosed, the better the cure rate. Youngsters less than age 10 years have a freedom from relapse of 80% at 26 years follow-up examination; adolescents in the 11 to 16 age group have a freedom from relapse or 74%; and adults aged 17 years or older have a freedom from relapse of 64%. These differences translate into significant survival differences as well, with children aged 10 years or younger and those aged 11 to 16 years having a 26-year survival of 74%, as compared to adults, who have a 37% survival (P = 0.003). These differences remain significant when comparing those with stage I and II disease, as opposed to those with advanced stage III and IV disease. Children present the greatest challenges with respect to staging and treatment. The older child with localized disease can be managed appropriately as an adult. However, for the younger child the use of low-dose radiation and multiagent chemotherapy is widely accepted. Using this approach, survival rates of 85% or greater are reported from many large institutional and cooperative group experiences. The goals of treatment today are cure of disease, with maximal quality of life and minimal complications from the treatment. The late effects of greatest importance to the youngest children are skeletal and bone growth abnormalities, sterility, and malignant tumor induction. Treatment programs today should be directed towards refining therapy to minimize sequelae while maximizing quality of life. These goals are best achieved when children are managed in regional centers with demonstrated expertise in the management of children with Hodgkin's disease. Whereas cure can be achieved in a large majority of children diagnosed with Hodgkin's disease, our challenge is cure, with the least sequelae and the greatest quality of life. "Children are not simply micro-adults, but have their own specific problems."

Adolescent↗
PubMed1991

Changing pattern of pulmonary metastases with adjuvant chemotherapy in patients with osteosarcoma: results from the multiinstitutional osteosarcoma study.

The multiinstitutional osteosarcoma study (MIOS), a randomized trial of adjuvant therapy for osteosarcoma with a concurrent control group, registered 113 patients from June 1982 to August 1984. Preliminary analysis of the study indicated a significant event-free survival advantage favoring immediate adjuvant chemotherapy, (P less than .001). For patients treated with surgery alone or with surgery and adjuvant chemotherapy, the lungs were involved in more than 80% of the relapses. Patients relapsing after surgery alone tended to relapse earlier (P less than .01), had more pulmonary nodules (P less than .01), and had more frequent bilateral pulmonary involvement (P less than .01) than those treated with immediate postsurgical adjuvant chemotherapy. However, patients relapsing after treatment with surgery alone experienced a significantly longer interval to further disease progression (P less than .01) and improved survival after relapse (P = .01) when compared with patients who relapsed after treatment with immediate adjuvant chemotherapy. The only factor predictive of survival after relapse was if the patient could be made surgically disease-free after initial relapse (P = .03).

Antineoplastic Agents↗
PubMed1991

Adjuvant chemotherapy of high-grade osteosarcoma of the extremity. Updated results of the Multi-Institutional Osteosarcoma Study.

The Multi-Institutional Osteosarcoma Study (MIOS) was designed to determine whether intensive multiagent adjuvant chemotherapy improves the outcome of patients with nonmetastatic high-grade osteosarcoma of the extremity as compared with concurrent controls. After definitive surgery of the primary tumor, patients were randomly assigned to immediate adjuvant chemotherapy or to observation without adjuvant treatment. Updated results of this trial indicate that the projected six-year event-free survival for the control group is 11% compared to 61% for the chemotherapy group (p less than 0.001). Similar results were observed in patients who declined randomization but who were followed according to the treatment arms of the protocol. When randomized and nonrandomized patients are pooled according to assigned treatment, a survival advantage favoring those patients treated with immediate adjuvant chemotherapy is apparent. An analysis of prognostic factors among patients receiving immediate adjuvant chemotherapy reveals that elevation of the serum lactic dehydrogenase at diagnosis is the factor most predictive of adverse outcome. Location of the primary site in the tibia confers a favorable prognosis. The authors conclude that the natural history of high-grade osteosarcoma of the extremity has not changed over the past two decades. The administration of immediate adjuvant chemotherapy has a significant favorable impact on event-free survival and should be recommended for all such patients.

Adult↗
PubMed1990

The t(1;14)(p34;q11) is nonrandom and restricted to T-cell acute lymphoblastic leukemia: a Pediatric Oncology Group study.

We report the nonrandom occurrence, frequency, and degree of immunophenotype association of the t(1;14)(p34;q11) in children with acute lymphoblastic leukemia (ALL). This chromosomal abnormality occurred in leukemia cells from 5 of 1,630 (0.3%) consecutive children with newly diagnosed ALL who were entered on a single Pediatric Oncology Group classification study (POG 8600) between January 1986 and February 1989. The frequency of the t(1;14) was 3% (5 of 168 cases) in children with T-cell ALL. All five cases had pseudodiploid karyotypes, and in 3 cases the t(1;14) was accompanied by a deletion of the long arm of chromosome 6. This translocation is of special interest because the breakpoint on chromosome 14 in band q11 corresponds to the assigned locus of the T-cell receptor alpha/delta chain gene. All five of our patients and three cases reported previously have had T-cell ALL. These findings, considered together, suggest that this translocation is specific for T-cell ALL and that a gene in the 1p34 region may play an important role in malignant transformation of thymocytes.

Adolescent↗
PubMed1990

Near-triploid and near-tetraploid acute lymphoblastic leukemia of childhood.

Cytogenetic and DNA flow cytometric analyses of leukemic cells from 1,971 children with newly diagnosed acute lymphoblastic leukemia (ALL) identified stem lines with modal chromosome numbers greater than 65 in 26 patients (1.3%). Near-triploidy (66 to 73 chromosomes) was found in six cases and near-tetraploidy (82 to 94 chromosomes) in 20. A striking morphologic finding was the presence of clumped chromatin with grooved nuclei or Rieder cell formation in 20 cases. Other than a slight excess of the pre-B immunophenotype, the near-triploid cases did not appear to differ substantially from the general ALL population in clinical features. In contrast, near-tetraploid cases were more often associated with a T-cell immunophenotype (47% v 14%, P less than .001) and L2 morphology (30% v 22%, P less than .01), and were older at diagnosis (median age, 8.6 v 4.8 years, P = .01) than cases with other ploidies. Moreover, an unusually high proportion of near-tetraploid cases tested (6 of 15) expressed one or more of the myeloid-associated antigens CD13, CD15, and CD33. Despite the use of contemporary intensive chemotherapy and short follow-up for most patients, 6 of the 20 near-tetraploid cases have relapsed or died. This study suggests that the near-tetraploid subtype differs from other cases of hyperdiploid greater than 50 ALL, which have been associated with a favorable prognosis.

Adolescent↗
PubMed1990

Results of treatment of childhood localized non-Hodgkin's lymphoma with combination chemotherapy with or without radiotherapy.

Combined radiotherapy and intensive chemotherapy have led to improved prognosis in children with non-Hodgkin's lymphoma, but the toxic effects of these forms of treatment are additive and seriously limit the benefits of their use. In an effort to limit the adverse acute and late effects of treatment, we conducted a randomized, controlled trial to determine whether irradiation of primary sites of involvement could safely be omitted from the treatment of children with localized non-Hodgkin's lymphoma (Stages I and II) who have a favorable prognosis. In addition, the chemotherapy regimen was less intense and shorter (eight months) than usual. A total of 129 patients were randomly assigned to receive either chemotherapy (vincristine, cyclophosphamide, doxorubicin, prednisone, mercaptopurine, and methotrexate) with irradiation (27 Gy) of the involved field (combined chemotherapy and radiotherapy) or chemotherapy alone. Half the patients have been followed for more than 38 months (range, 13 to 68), and the projected disease-free survival (+/- SE) at four years among patients assigned to chemotherapy alone is 87.9 +/- 8.8 percent, as compared with 87.3 +/- 9.4 percent among patients assigned to combined therapy (P = 0.44). The majority of patients tolerated therapy very well, although the toxic effects of treatment (myelosuppression, mucositis, and infection) were significantly worse among patients who received the combination of chemotherapy and radiotherapy. We conclude that most children with localized non-Hodgkin's lymphoma can be cured by a chemotherapy regimen of reduced intensity and duration. Radiotherapy can be safely omitted from the therapy of such children without substantially jeopardizing their excellent chance of cure.

Antineoplastic Combined Chemotherapy Protocols↗