Michael Link

All Publications

• A study of the mutational landscape of pediatric-type follicular lymphoma and pediatric nodal marginal zone lymphoma. Modern pathology Ozawa, M. G., Bhaduri, A., Chisholm, K. M., Baker, S. A., Ma, L., Zehnder, J. L., Luna-Fineman, S., Link, M. P., Merker, J. D., Arber, D. A., Ohgami, R. S. 2016; 29 (10): 1212-1220

  Abstract

  Pediatric-type follicular lymphoma and pediatric marginal zone lymphoma are two of the rarest B-cell lymphomas. These lymphomas occur predominantly in the pediatric population and show features distinct from their more common counterparts in adults: adult-type follicular lymphoma and adult-type nodal marginal zone lymphoma. Here we report a detailed whole-exome deep sequencing analysis of a cohort of pediatric-type follicular lymphomas and pediatric marginal zone lymphomas. This analysis revealed a recurrent somatic variant encoding p.Lys66Arg in the transcription factor interferon regulatory factor 8 (IRF8) in 3 of 6 cases (50%) of pediatric-type follicular lymphoma. This specific point mutation was not detected in pediatric marginal zone lymphoma or in adult-type follicular lymphoma. Additional somatic point mutations in pediatric-type follicular lymphoma were observed in genes involved in transcription, intracellular signaling, and cell proliferation. In pediatric marginal zone lymphoma, no recurrent mutation was identified; however, somatic point mutations were observed in genes involved in cellular adhesion, cytokine regulatory elements, and cellular proliferation. A somatic variant in AMOTL1, a recurrently mutated gene in splenic marginal zone lymphoma, was also identified in a case of pediatric marginal zone lymphoma. The overall non-synonymous mutational burden was low in both pediatric-type follicular lymphoma and pediatric marginal zone lymphoma (4.6 mutations per exome). Altogether, these findings support a distinctive genetic basis for pediatric-type follicular lymphoma and pediatric marginal zone lymphoma when compared with adult subtypes and to one another. Moreover, identification of a recurrent point mutation in IRF8 provides insight into a potential driver mutation in the pathogenesis of pediatric-type follicular lymphoma with implications for novel diagnostic or therapeutic strategies.Modern Pathology advance online publication, 24 June 2016; doi:10.1038/modpathol.2016.102.

  View details for DOI 10.1038/modpathol.2016.102

  View details for PubMedID 27338637

• Safety Report of Ferumoxytol for Magnetic Resonance Imaging in Children and Young Adults INVESTIGATIVE RADIOLOGY Muehe, A. M., Feng, D., von Eyben, R., Luna-Fineman, S., Link, M. P., Muthig, T., Huddleston, A. E., Neuwelt, E. A., Daldrup-Link, H. E. 2016; 51 (4): 221-227

  Abstract

  The aim of this study was to assess the safety profile of ferumoxytol as an intravenous magnetic resonance imaging contrast agent in children.We prospectively evaluated the safety of ferumoxytol administrations as an "off-label" contrast agent for magnetic resonance imaging in nonrandomized phase 4 clinical trials at 2 centers. From September 2009 to February 2015, 49 pediatric patients (21 female and 28 male, 5-18 years) and 19 young adults (8 female and 11 male, 18-25 years) were reported under an investigator-initiated investigational new drug investigation with institutional review board approval, in health insurance portability and accountability act compliance, and after written informed consent of the child's legal representative or the competent adult patient was obtained. Patients received either a single dose (5 mg Fe/kg) or up to 4 doses of ferumoxytol (0.7-4 mg Fe/kg) intravenously, which were approximately equivalent to one third of the dose for anemia treatment. We monitored vital signs and adverse events directly for up to 1 hour after injection. In addition, we examined weekly vitals, hematologic, renal, and liver serum panels for 1 month after injection in over 20 pediatric patients. At fixed time points before and after ferumoxytol injection, data were evaluated for significant differences by a repeated measures linear mixed model.Four mild adverse events, thought to be related to ferumoxytol, were observed within 1 hour of 85 ferumoxytol injections: 2 episodes of mild hypotension and 1 case of nausea in 65 injections in pediatric patients without related clinical symptoms. One young adult patient developed warmness and erythema at the injection site. All adverse events were self-resolving. No spontaneous serious adverse events were reported. At a dose of 5 mg Fe/kg or lower, intravenous ferumoxytol injection had no clinical relevance or statistically significant effect (P > 0.05) on vital signs, hematological parameters, kidney function, or liver enzymes within 1 month of the injection.Ferumoxytol was overall well tolerated among 49 pediatric and 19 young adult patients experiencing various tumors or kidney transplants without major adverse events or signs of hematologic and kidney impairment or liver toxicity. Larger studies are needed to determine the incidence of anaphylactic reactions.

  View details for DOI 10.1097/RLI.0000000000000230

  View details for Web of Science ID 000372451200002

  View details for PubMedCentralID PMC4783197

• Subcutaneous Panniculitis-Like T-Cell Lymphoma: Pediatric Case Series Demonstrating Heterogeneous Presentation and Option for Watchful Waiting PEDIATRIC BLOOD & CANCER Johnston, E. E., LeBlanc, R. E., Kim, J., Chung, J., Balagtas, J., Kim, Y. H., Link, M. P. 2015; 62 (11): 2025-2028

  View details for DOI 10.1002/pbc.25626

  View details for Web of Science ID 000364581100029

  View details for PubMedID 26146844

• Primary Cutaneous Gamma-Delta T-Cell Lymphoproliferative Disorder in a 3-Year-Old Boy. American Journal of dermatopathology Soon, C. W., Link, M., Kim, Y. H., Kim, J. 2015; 37 (7): 567-569

  Abstract

  Primary cutaneous gamma-delta T-cell lymphoma (PCGD-TCL) is a rare disorder, constituting less than 1% of primary cutaneous lymphomas. Most cases occur in adults and may present as plaques or nodules with ulceration. Here we describe an unusual case of PCGD-TCL in a 3-year-old boy who presented with asymptomatic subcutaneous nodules. To our knowledge, this report represents one of the youngest reported patients with gamma-delta lymphoma/lymphoproliferative disorder. In addition, our patient has an indolent clinical presentation with greater than 1 year clinical follow-up. Because gamma-delta T-cell lymphomas are exceedingly rare in children, we acknowledge that the clinical course/outcome in young patients is still unclear. We hope to add to the recognition that PCGD-TCLs demonstrate a wide clinical spectrum of disease with relatively indolent presentations in some cases.

  View details for DOI 10.1097/DAD.0000000000000185

  View details for PubMedID 25072685

• Management of Nodular Lymphocyte Predominant Hodgkin Lymphoma in the Modern Era INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS King, M. T., Donaldson, S. S., Link, M. P., Natkunam, Y., Advani, R. H., Hoppe, R. T. 2015; 92 (1): 67-75

  Abstract

  To analyze treatment outcomes for nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) at a single institution.Patients with newly diagnosed NLPHL between 1996 and 2013 were reviewed retrospectively. Patients treated before 1996 were excluded because the majority received extended field radiation therapy (RT) alone.Fifty-five patients (22 ≤ 21 years old) were identified. The median follow-up time was 6.8 years. Among 37 patients with limited-stage (I-II) disease, treatments included involved field RT at a median dose of 36 Gy (n=9), rituximab monotherapy (n=9), observation (n=3), and response-adaptive therapy (n=16), in which the RT dose was reduced from 25.5 Gy to 15 Gy or was eliminated based on interim imaging after chemotherapy. The 5-year progression-free survival (PFS) was 76.4% (95% confidence interval [CI], 63.1-92.4). Nine patients experienced progression, including 5 receiving rituximab, 2 undergoing observation, and 2 receiving response-adaptive therapy. Rituximab was associated with an inferior PFS compared with RT alone (P=.02). The difference in PFS between response-adaptive therapy and RT alone was not statistically significant (P=.39). Among 18 patients with advanced-stage (III-IV) disease, treatments included chemotherapy alone (n=3), combined modality therapy (CMT) (n=2), response-adaptive therapy (n=2), rituximab (n=7), and observation (n=4). The 5-year PFS was 29.9% (CI, 13.3-67.4). Twelve patients experienced progression, including 1 receiving chemotherapy, 1 receiving CMT, 6 receiving rituximab, and 4 undergoing observation. There was no significant PFS difference between rituximab and non-rituximab therapies (P=.19) within the caveat of small sample sizes. In the entire cohort, 9 patients (3 with limited disease, 6 with advanced disease) experienced large cell transformation (LCT). Seven patients died; of those, 5 died with LCT.For limited disease, response-adaptive therapy demonstrated comparable outcomes with RT alone. Rituximab monotherapy resulted in inferior outcomes for limited disease and a high relapse rate for advanced disease.

  View details for DOI 10.1016/j.ijrobp.2015.02.001

  View details for Web of Science ID 000353988200011

  View details for PubMedID 25863755

• The utility of IgM, CD21, HGAL and LMO2 in the diagnosis of pediatric follicular lymphoma HUMAN PATHOLOGY Karnik, T., Ozawa, M. G., Lefterova, M., Luna-Fineman, S., Alvarez, E., Link, M., Zehnder, J. L., Arber, D. A., Ohgami, R. S. 2015; 46 (4): 629-633

  Abstract

  Pediatric follicular lymphoma (pFL) is a rare neoplasm with features differing from follicular lymphoma arising in adults. Here, we describe a rare case of pFL that showed morphologic features partially overlapping with progressive transformation of germinal centers and reactive follicular hyperplasia. As typical of pFL, neoplastic B cells within follicles did not express B-cell leukemia/lymphoma 2 (BCL2). However, this case showed additional distinctive abnormal findings, which contributed to the diagnosis: (1) diffuse and uniform staining of immunoglobulin M (IgM) on cells within and outside of follicles, (2) abnormally dim expression of CD21 on follicular dendritic cells, and (3) expression of human germinal center-associated lymphoma (HGAL) and LIM domain only 2 (LMO2) on B cells in interfollicular and follicular areas. This case demonstrates the utility of these abnormal features, which can be seen in adult- or usual-type follicular lymphoma, in the diagnosis of pFL. Further studies are necessary to evaluate the significance of these findings in other cases of pFL.

  View details for DOI 10.1016/j.humpath.2014.12.016

  View details for Web of Science ID 000352117000020

  View details for PubMedID 25701230

• Improved outcomes after autologous bone marrow transplantation for children with relapsed or refractory hodgkin lymphoma: twenty years experience at a single institution. Biology of blood and marrow transplantation Garfin, P. M., Link, M. P., Donaldson, S. S., Advani, R. H., Luna-Fineman, S., Kharbanda, S., Porteus, M., Weinberg, K. I., Agarwal-Hashmi, R. 2015; 21 (2): 326-334

  Abstract

  The purpose of this study is to evaluate the survival of pediatric patients undergoing autologous bone marrow transplantation (auBMT) for relapsed or refractory Hodgkin lymphoma (rrHL) and to identify factors that might contribute to their outcome. We reviewed the records and clinical course of 89 consecutive rrHL patients ≤ 21 years old who underwent auBMT at Stanford Hospitals and Clinics and the Lucile Packard Children's Hospital, Stanford between 1989 and 2012. We investigated, by multiple analyses, patient, disease, and treatment characteristics associated with outcome. Endpoints were 5-year overall and event-free survival. Our findings include that cyclophosphamide, carmustine, and etoposide (CBV) as a conditioning regimen for auBMT is effective for most patients ≤ 21 years old with rrHL (5-year overall survival, 71%). Transplantation after the year 2001 was associated with significantly improved overall survival compared with our earlier experience (80% compared with 65%). Patients with multiply relapsed disease or with disease not responsive to initial therapy fared less well compared with those with response to initial therapy or after first relapse. Administration of post-auBMT consolidative radiotherapy (cRT) also appears to contribute to improved survival. We are able to conclude that high-dose chemotherapy with CBV followed by auBMT is effective for the treatment of rrHL in children and adolescents. Survival for patients who undergo auBMT for rrHL has improved significantly. This improvement may be because of patient selection and improvements in utilization of radiotherapy rather than improvements in chemotherapy. Further investigation is needed to describe the role of auBMT across the entire spectrum of patients with rrHL and to identify the most appropriate preparative regimen with or without cRT therapy in the treatment of rrHL in young patients.

  View details for DOI 10.1016/j.bbmt.2014.10.020

  View details for PubMedID 25445024

• Value of 18F-FDG PET and PET/CT for evaluation of pediatric malignancies. Journal of nuclear medicine : official publication, Society of Nuclear Medicine Uslu, L., Donig, J., Link, M., Rosenberg, J., Quon, A., Daldrup-Link, H. E. 2015; 56 (2): 274-286

  Abstract

  Successful management of solid tumors in children requires imaging tests for accurate disease detection, characterization, and treatment monitoring. Technologic developments aim toward the creation of integrated imaging approaches that provide a comprehensive diagnosis with a single visit. These integrated diagnostic tests not only are convenient for young patients but also save direct and indirect health-care costs by streamlining procedures, minimizing hospitalizations, and minimizing lost school or work time for children and their parents. (18)F-FDG PET/CT is a highly sensitive and specific imaging modality for whole-body evaluation of pediatric malignancies. However, recent concerns about ionizing radiation exposure have led to a search for alternative imaging methods, such as whole-body MR imaging and PET/MR. As we develop new approaches for tumor staging, it is important to understand current benchmarks. This review article will synthesize the current literature on (18)F-FDG PET/CT for tumor staging in children, summarizing questions that have been solved and providing an outlook on unsolved avenues.

  View details for DOI 10.2967/jnumed.114.146290

  View details for PubMedID 25572088

• Value of F-18-FDG PET and PET/CT for Evaluation of Pediatric Malignancies JOURNAL OF NUCLEAR MEDICINE Uslu, L., Donig, J., Link, M., Rosenberg, J., Quon, A., Daldrup-Link, H. E. 2015; 56 (2): 274-286

  View details for DOI 10.2967/jnumed.114.146290

  View details for Web of Science ID 000349324300030

• Milestones in the Curability of Pediatric Cancers JOURNAL OF CLINICAL ONCOLOGY Hudson, M. M., Link, M. P., Simone, J. V. 2014; 32 (23): 2391-2397

  View details for DOI 10.1200/JCO.2014.55.6571

  View details for Web of Science ID 000340556400002

  View details for PubMedID 24733794

• Increased utilization of pediatric specialty care: a population study of pediatric oncology inpatients in california. Journal of pediatric hematology/oncology Chamberlain, L. J., Pineda, N., Winestone, L., Saynina, O., Rangaswami, A., Link, M., Wise, P. H. 2014; 36 (2): 99-107

  Abstract

  To examine inpatient utilization of pediatric cancer specialty centers (PCSCs) by pediatric oncology patients.We performed a retrospective (1999 to 2010) population-based analysis of oncology hospitalizations for pediatric patients aged 0 through 18 years using the California Office of Statewide Health Planning and Development database. Logistic regression examined hospitalization at 29 PCSCs and variables of age, sex, tumor type, payer, race, income, and distance to admission site.Analysis of 103,961 pediatric oncology discharges revealed that 93% occurred at PCSCs. These sites experienced a 20% increase in pediatric oncology discharges, conversely non-PCSCs exhibited a 70% decrease (P<0.0001). Multivariate analyses revealed increased utilization with young age (odds ratio [OR], 4.58; 95% CI, 3.88-5.42), African American (OR, 1.26; 95% CI, 1.11-1.43), and middle income (OR, 1.36; 95% CI, 1.29-1.45). Decreased utilization was seen for females (OR, 0.88; 95% CI, 0.84-0.93) and Hispanics (OR, 0.72; 95% CI, 0.68-0.77). Payer and proximity were not significantly associated with change in utilization. Tumor types less likely to utilize a PCSC included germ cell, solid, and central nervous system tumors. Adolescents were >3 times less likely to be treated at a PCSC.Inpatient pediatric oncology care in California has become increasingly regionalized with the vast majority of patients accessing PCSCs. However, variability in hospitalizations of adolescent patients and children not treated in PCSCs deserve further evaluation.

  View details for DOI 10.1097/01.mph.0000438027.07467.f1

  View details for PubMedID 24517965

• Adolescent and Young Adult Oncology, Version 2.2014 JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Coccia, P. F., Pappo, A. S., Altman, J., Bhatia, S., Borinstein, S. C., Flynn, J., Frazier, A. L., George, S., Goldsby, R., Hayashi, R., Huang, M. S., Johnson, R. H., Beaupin, L. K., Link, M. P., Oeffinger, K. C., Orr, K. M., Reed, D., Spraker, H. L., Thomas, D. A., von Mehren, M., Wechsler, D. S., Whelan, K. F., Zebrack, B., Shead, D. A., Sundar, H. 2014; 12 (1): 21-32

  Abstract

  The NCCN Guidelines Insights on Adolescent and Young Adult (AYA) Oncology discuss the fertility and endocrine issues that are relevant to the management of AYA patients with cancer. Fertility preservation should be an essential part in the treatment of AYA patients with cancer. The NCCN Guidelines recommend discussion of fertility preservation and contraception before the start of treatment. Oophoropexy and embryo cryopreservation are the 2 established options for fertility preservation in women. Semen cryopreservation before the start of treatment is the most reliable and well-established method of preserving fertility in men. AYA women with cancer also have unique contraception needs, depending on the type of cancer, its treatment, and treatment-related complications. Management of cancer during pregnancy poses significant diagnostic and therapeutic challenges for both the patient and the physician. AYA women diagnosed with cancer during pregnancy require individualized treatment from a multidisciplinary team involving medical, surgical, radiation, and gynecologic oncologists; obstetricians; and perinatologists.

  View details for Web of Science ID 000330333200004

  View details for PubMedID 24453290

• Relapse after treatment of pediatric hodgkin lymphoma: Outcome and role of surveillance after end of therapy PEDIATRIC BLOOD & CANCER Friedmann, A. M., Wolfson, J. A., Hudson, M. M., Weinstein, H. J., Link, M. P., Billett, A., Larsen, E. C., Yock, T., Donaldson, S. S., Marcus, K., Krasin, M. J., Howard, S. C., Metzger, M. L. 2013; 60 (9): 1458-1463

  Abstract

  The outcome of treatment for pediatric Hodgkin lymphoma (HL) is excellent using chemotherapy and radiation. However, a minority of patients will relapse after treatment, but additional therapy achieves durable second remission in many cases. The optimal surveillance strategy after modern therapy for HL has not been well defined.We reviewed the outcomes of pediatric patients with HL treated between 1990 and 2006 to determine the primary event that led to the detection of relapse. We determined the probability of relapse detection by routine follow-up procedures, including history, physical examination, laboratory tests, and imaging, and determined the impact of each of these screening methods on the likelihood of survival after relapse.Relapse occurred in 64 of 402 evaluable patients (15.9%) at a median of 1.7 years from the time of diagnosis. The majority of relapses (60%) were diagnosed at a routine visit, and patient complaint was the most common initial finding that led to a diagnosis of relapse (47% of relapses). An abnormal finding on physical examination was the primary event in another 17% of relapses, and imaging abnormalities led to the diagnosis in the remaining 36%. Laboratory abnormalities were never the primary finding. The method of detection of relapse and timing (whether detected at a routine visit or an extra visit) did not impact survival.In pediatric HL, most relapses are identified through history and physical examination. Frequent imaging of asymptomatic patients does not appear to impact survival and is probably not warranted.

  View details for DOI 10.1002/pbc.24568

  View details for Web of Science ID 000321703900078

  View details for PubMedID 23677874

• Autologous Transplantation for Hodgkin disease: A Tale of Two Eras BMT Tandem Meetings Garfin, P. M., Luna-Fineman, S., Amylon, M., Kharbanda, S., Weinberg, K. I., Willert, J. R., Porteus, M., Link, M., Agarwal, R. ELSEVIER SCIENCE INC. 2013: S247–S247

  View details for Web of Science ID 000314441900267

• The Impact of Drug Shortages on Children with Cancer - The Example of Mechlorethamine NEW ENGLAND JOURNAL OF MEDICINE Metzger, M. L., Billett, A., Link, M. P. 2012; 367 (26): 2461-2463

  View details for DOI 10.1056/NEJMp1212468

  View details for Web of Science ID 000312714200001

  View details for PubMedID 23268661

• Extremely low-frequency magnetic fields and survival from childhood acute lymphoblastic leukemia: an international follow-up study BLOOD CANCER JOURNAL Schuz, J., Grell, K., Kinsey, S., Linet, M. S., Link, M. P., Mezei, G., Pollock, B. H., ROMAN, E., Zhang, Y., McBride, M. L., Johansen, C., Spix, C., Hagihara, J., Saito, A. M., Simpson, J., Robison, L. L., Dockerty, J. D., Feychting, M., Kheifets, L., Frederiksen, K. 2012; 2

  Abstract

  A previous US study reported poorer survival in children with acute lymphoblastic leukemia (ALL) exposed to extremely low-frequency magnetic fields (ELF-MF) above 0.3 μT, but based on small numbers. Data from 3073 cases of childhood ALL were pooled from prospective studies conducted in Canada, Denmark, Germany, Japan, UK and US to determine death or relapse up to 10 years from diagnosis. Adjusting for known prognostic factors, we calculated hazard ratios (HRs) and 95% confidence intervals (CI) for overall survival and event-free survival for ELF-MF exposure categories and by 0.1 μT increases. The HRs by 0.1 μT increases were 1.00 (CI, 0.93-1.07) for event-free survival analysis and 1.04 (CI, 0.97-1.11) for overall survival. ALL cases exposed to >0.3 μT did not have a poorer event-free survival (HR=0.76; CI, 0.44-1.33) or overall survival (HR=0.96; CI, 0.49-1.89). HRs varied little by subtype of ALL. In conclusion, ELF-MF exposure has no impact on the survival probability or risk of relapse in children with ALL.

  View details for DOI 10.1038/bcj.2012.43

  View details for Web of Science ID 000313368200002

  View details for PubMedID 23262804

• Adolescent and young adult oncology. Clinical practice guidelines in oncology. Journal of the National Comprehensive Cancer Network Coccia, P. F., Altman, J., Bhatia, S., Borinstein, S. C., Flynn, J., George, S., Goldsby, R., Hayashi, R., Huang, M. S., Johnson, R. H., Beaupin, L. K., Link, M. P., Oeffinger, K. C., Orr, K. M., Pappo, A. S., Reed, D., Spraker, H. L., Thomas, D. A., von Mehren, M., Wechsler, D. S., Whelan, K. F., Zebrack, B. J., Sundar, H., Shead, D. A. 2012; 10 (9): 1112-1150

  Abstract

  Cancer is the leading cause of death among the adolescent and young adult (AYA) population, excluding homicide, suicide, or unintentional injury. AYA patients should be managed by a multidisciplinary team of health care professionals who are well-versed in the specific developmental issues relevant to this patient population. The recommendations for age-appropriate care outlined in these NCCN Guidelines include psychosocial assessment, a discussion of infertility risks associated with treatment and options for fertility preservation, genetic and familial risk assessment for all patients after diagnosis, screening and monitoring of late effects in AYA cancer survivors after successful completion of therapy, and palliative care and end-of-life considerations for patients for whom curative therapy fails.

  View details for PubMedID 22956810

• Adolescent and Young Adult Oncology JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Coccia, P. F., Altman, J., Bhatia, S., Borinstein, S. C., Flynn, J., George, S., Goldsby, R., Hayashi, R., Huang, M. S., Johnson, R. H., Beaupin, L. K., Link, M. P., Oeffinger, K. C., Orr, K. M., Pappo, A. S., Reed, D., Spraker, H. L., Thomas, D. A., von Mehren, M., Wechsler, D. S., Whelan, K. F., Zebrack, B. J. 2012; 10 (9): 1112-1150

  View details for Web of Science ID 000308575200009

• ALK+ anaplastic large cell lymphoma exhibits phosphatidylinositol-3 kinase/akt activity with retained but inactivated PTEN-A report from the Children's Oncology Group PEDIATRIC BLOOD & CANCER Thakral, C., Hutchison, R. E., Shrimpton, A., Barrett, D., Laver, J., Link, M., Halleran, D. R., Hudson, S. 2012; 59 (3): 440-447

  Abstract

  ALK+ anaplastic large cell lymphoma (ALCL) is usually a disease of young patients. We investigated phosphatidylinositol-3 kinase (PI3K)/Akt pathway-associated factors in pediatric cases and cell lines.Patient materials consisted of tissue slides of ALK+/CD30+ ALCL from 33 patients treated on Pediatric Oncology Group protocols (9219, n = 8 and 9315, n = 25). Slides were examined by immunohistochemistry for phospho(p)-Akt and PTEN, the primary feedback regulator of the pathway, as well as for p27kip1 and stathmin-1. ALCL cell lines SUDHL-1 and Karpas-299 were examined for ALK, pALK, pAkt, p27/Kip1, PTEN, pPTEN, CD30, pSTAT3, and pSTAT5; ALK inhibition was performed using compound PF-2341066 and PTEN genes were sequenced.A majority of patients expressed pAkt, PTEN, and stathmin, with p27kip1 levels less than controls. Cell lines showed expression of ALK, pALK, pSTAT3, pSTAT5, CD30, pAkt, PTEN, and pPTEN, with p27 slightly less than positive controls, and germline PTEN DNA. There was evidence of phosphorylated PTEN (pPTEN) associated with inhibited function. Pharmacologic inhibition of activated ALK diminished pSTAT3, pSTAT5, and CD30 expression but not pAkt or pPTEN in cultured cell lines.We conclude that the PI3K/Akt pathway is activated in many, though not all, pediatric ALK+ ALCL. Our data suggest that activation of this pathway involves post-translational regulation of PTEN. Pharmacologic inhibition of activated ALK does not reduce modest levels of activated Akt as it does with the more abundant levels of activated STAT3 or STAT5. Future therapy of ALCL might, in selected patients, best combine agents inhibiting PI3K/Akt with those targeting ALK.

  View details for DOI 10.1002/pbc.24153

  View details for Web of Science ID 000306314400006

  View details for PubMedID 22488797

• Association Between Radiotherapy vs No Radiotherapy Based on Early Response to VAMP Chemotherapy and Survival Among Children With Favorable-Risk Hodgkin Lymphoma JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Metzger, M. L., Weinstein, H. J., Hudson, M. M., Billett, A. L., Larsen, E. C., Friedmann, A., Howard, S. C., Donaldson, S. S., Krasin, M. J., Kun, L. E., Marcus, K. J., Yock, T. I., Tarbell, N., Billups, C. A., Wu, J., Link, M. P. 2012; 307 (24): 2609-2616

  Abstract

  More than 90% of children with favorable-risk Hodgkin lymphoma can achieve long-term survival, yet many will experience toxic effects from radiation therapy. Pediatric oncologists strive for maintaining excellent cure rates while minimizing toxic effects.To evaluate the efficacy of 4 cycles of vinblastine, Adriamycin (doxorubicin), methotrexate, and prednisone (VAMP) in patients with favorable-risk Hodgkin lymphoma who achieve a complete response after 2 cycles and do not receive radiotherapy.Multi-institutional, unblinded, nonrandomized single group phase 2 clinical trial to assess the need for radiotherapy based on early response to chemotherapy. Eighty-eight eligible patients with Hodgkin lymphoma stage I and II (<3 nodal sites, no B symptoms, mediastinal bulk, or extranodal extension) enrolled between March 3, 2000, and December 9, 2008. Follow-up data are current to March 12, 2012.The 47 patients who achieved a complete response after 2 cycles received no radiotherapy, and the 41 with less than a complete response were given 25.5 Gy-involved-field radiotherapy.Two-year event-free survival was the primary outcome measure. A 2-year event-free survival of greater than 90% was desired, and 80% was considered to be unacceptably low.Two-year event-free survival was 90.8% (95% CI, 84.7%-96.9%). For patients who did not require radiotherapy, it was 89.4% (95% CI, 80.8%-98.0%) compared with 92.5% (95% CI, 84.5%-100%) for those who did (P = .61). Most common acute adverse effects were neuropathic pain (2% of patients), nausea or vomiting (3% of patients), neutropenia (32% of cycles), and febrile neutropenia (2% of patients). Nine patients (10%) were hospitalized 11 times (3% of cycles) for febrile neutropenia or nonneutropenic infection. Long-term adverse effects after radiotherapy were asymptomatic compensated hypothyroidism in 9 patients (10%), osteonecrosis and moderate osteopenia in 2 patients each (2%), subclinical pulmonary dysfunction in 12 patients (14%), and asymptomatic left ventricular dysfunction in 4 patients (5%). No second malignant neoplasms were observed.Among patients with favorable-risk Hodgkin lymphoma and a complete early response to chemotherapy, the use of limited radiotherapy resulted in a high rate of 2-year event-free survival.clinicaltrials.gov Identifier: NCT00145600.

  View details for Web of Science ID 000305692600029

  View details for PubMedID 22735430

  View details for PubMedCentralID PMC3526806

• Stanford V chemotherapy and involved field radiotherapy for children and adolescents with unfavorable risk Hodgkin lymphoma: Results of a multi-institutional prospective clinical trial 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Metzger, M., Billett, A., Friedmann, A. M., Krasin, M. J., Howard, S. C., Weinstein, H. J., Larsen, E., Marcus, K. C., Billups, C., Wu, J., Donaldson, S. S., Link, M. P., Hudson, M. M. AMER SOC CLINICAL ONCOLOGY. 2012

  View details for Web of Science ID 000318009801580

• Chemotherapy Drug Shortages in the United States: Genesis and Potential Solutions JOURNAL OF CLINICAL ONCOLOGY Link, M. P., Hagerty, K., Kantarjian, H. M. 2012; 30 (7): 692-694

  View details for DOI 10.1200/JCO.2011.41.0936

  View details for Web of Science ID 000302625400009

  View details for PubMedID 22291078

• Complete Ocular Paresis in a Child with Posterior Fossa Syndrome PEDIATRIC NEUROSURGERY Afshar, M., Link, M., Edwards, M. S., Fisher, P. G., Fredrick, D., Monje, M. 2012; 48 (1): 51-54

  Abstract

  Posterior fossa syndrome (PFS), also known as cerebellar affective syndrome, is characterized by emotional lability and decreased speech production following injury or surgery to the cerebellum. Rarely, oculomotor dysfunction has been described in association with PFS. Here, we report a case of complete ocular paresis associated with PFS in an 11-year-old male following medulloblastoma resection.

  View details for DOI 10.1159/000339382

  View details for Web of Science ID 000309885700010

  View details for PubMedID 22906880

• Second Malignant Neoplasms in Survivors of Pediatric Hodgkin's Lymphoma Treated With Low-Dose Radiation and Chemotherapy JOURNAL OF CLINICAL ONCOLOGY O'Brien, M. M., Donaldson, S. S., Balise, R. R., Whittemore, A. S., Link, M. P. 2010; 28 (7): 1232-1239

  Abstract

  Survivors of childhood Hodgkin's lymphoma (HL) are at risk for second malignant neoplasms (SMNs). It is theorized that this risk may be attenuated in patients treated with lower doses of radiation. We report the first long-term outcomes of a cohort of pediatric survivors of HL treated with chemotherapy and low-dose radiation.Pediatric patients with HL (n = 112) treated at Stanford from 1970 to 1990 on two combined modality treatment protocols were identified. Treatment included six cycles of chemotherapy with 15 to 25.5 Gy involved-field radiation with optional 10 Gy boosts to bulky sites. Follow-up through September 1, 2007, was obtained from retrospective chart review and patient questionnaires.One hundred ten children completed HL therapy; median follow-up was 20.6 years. Eighteen patients developed one or more SMNs, including four leukemias, five thyroid carcinomas, six breast carcinomas, and four sarcomas. Cumulative incidence of first SMN was 17% (95% CI, 10.5 to 26.7) at 20 years after HL diagnosis. The standard incidence ratio for any SMN was 22.9 (95% CI, 14.2 to 35) with an absolute excess risk of 93.7 cases per 10,000 person-years. All four secondary leukemias were fatal. For those with second solid tumors, the mean (+/- SE) 5-year disease-free and overall survival were 76% +/- 12% and 85% +/- 10% with median follow-up 5 years from SMN diagnosis.Despite treatment with low-dose radiation, children treated for HL remain at significant risk for SMN. Sarcomas, breast and thyroid carcinomas occurred with similar frequency and latency as found in studies of children with HL who received high-dose radiation.

  View details for DOI 10.1200/JCO.2009.24.8062

  View details for Web of Science ID 000274892500025

  View details for PubMedID 20124178

• The Impact of the Privacy Rule on Cancer Research: Variations in Attitudes and Application of Regulatory Standards JOURNAL OF CLINICAL ONCOLOGY Goss, E., Link, M. P., Bruinooge, S. S., Lawrence, T. S., Tepper, J. E., Runowicz, C. D., Schilsky, R. L. 2009; 27 (24): 4014-4020

  Abstract

  The American Society of Clinical Oncology (ASCO) Cancer Research Committee designed a qualitative research project to assess the attitudes of cancer researchers and compliance officials regarding compliance with the US Privacy Rule and to identify potential strategies for eliminating perceived or real barriers to achieving compliance.A team of three interviewers asked 27 individuals (13 investigators and 14 compliance officials) from 13 institutions to describe the anticipated approach of their institutions to Privacy Rule compliance in three hypothetical research studies.The interviews revealed that although researchers and compliance officials share the view that patients' cancer diagnoses should enjoy a high level of privacy protection, there are significant tensions between the two groups related to the proper standards for compliance necessary to protect patients. The disagreements are seen most clearly with regard to the appropriate definition of a "future research use" of protected health information in biospecimen and data repositories and the standards for a waiver of authorization for disclosure and use of such data.ASCO believes that disagreements related to compliance and the resulting delays in certain projects and abandonment of others might be eased by additional institutional training programs and consultation on Privacy Rule issues during study design. ASCO also proposes the development of best practices documents to guide 1) creation of data repositories, 2) disclosure and use of data from such repositories, and 3) the design of survivorship and genetics studies.

  View details for DOI 10.1200/JCO.2009.22.3289

  View details for Web of Science ID 000269064300024

  View details for PubMedID 19620480

• Non-anaplastic peripheral T-cell lymphoma in childhood and adolescence: A children's oncology group study 95th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology Hutchison, R. E., Laver, J. H., Chang, M., Muzzafar, T., Desai, S., Murphy, S., Schwenn, M., Shuster, J., Link, M. P. WILEY PERIODICALS, INC. 2008: 29–33

  Abstract

  Peripheral T-cell lymphomas (PTCL) other than anaplastic large cell lymphoma (ALCL) are rare in young patients. While a high proportion of adults with PTCL have poor risk disease, pediatric PTCL is not well characterized. This study examines the outcome of localized and advanced PTCL in pediatric patients treated in standardized fashion.We identified 20 pediatric patients diagnosed with PTCL whose tumor cells did not express CD30 and/or ALK, as determined by immunohistochemistry, between 1992 and 2000 on one of two treatment protocols for localized NHL (POG 9219) or advanced stage large cell lymphoma (POG 9315). All cases were centrally reviewed.The median age was 12.6 (range 0.7-16.9)-9 male and 11 female. Histological subtypes in the WHO Classification included PTCL, unspecified (12), extra-nodal NK/T-cell lymphoma of nasal type (4), subcutaneous panniculitis-like T cell lymphoma (1) and enteropathy-type T-cell lymphoma (1). Two cases exhibited both T-cell and histiocyte markers and were reclassified as histiocytic sarcoma per the WHO, although T-lineage remains possible. Of 10 patients with localized disease, only two relapsed and 9 survive. Of 10 patients with advanced disease, six relapsed and five (50%) survive.These results suggest that localized PTCL in children and adolescents is frequently cured with modern therapy, but that advanced stage cases may require novel therapy.

  View details for DOI 10.1002/pbc.21543

  View details for Web of Science ID 000255816800007

  View details for PubMedID 18300314

• Nodular lymphocyte-predominant Hodgkin lymphoma presenting as fulminant hepatic failure in a pediatric patient: A case report with pathologic, immunophenotypic, and molecular findings APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY Woolf, K. M., Wei, M. C., Link, M. P., Arber, D. A., Warnke, R. A. 2008; 16 (2): 196-201

  Abstract

  A 7-year-old boy presented with fulminant hepatic failure requiring liver transplant. Serologic testing ruled out infectious and autoimmune causes. During transplant surgery he was found to have enlarged periportal lymph nodes that were biopsied. Nodular lymphocyte-predominant Hodgkin lymphoma was diagnosed based on histologic examination of the lymph node and liver. The L&H cells within the lymph node were positive for CD20 whereas those within the liver were not, although they were positive for other B-cell markers. After extensive work-up, the cause of liver failure could only be attributed to the involvement by lymphoma. In addition, B-cell clonality was established among the neoplastic cells with the same clone detected in all sampled tissues. Hodgkin lymphoma as a cause of hepatic failure is rare and has not been previously reported in a pediatric patient.

  View details for Web of Science ID 000253788700016

  View details for PubMedID 18227720

• Osteosarcoma: The addition of muramyl tripeptide to chemotherapy improves overall survival - A report from the Children's Oncology Group JOURNAL OF CLINICAL ONCOLOGY Meyers, P. A., Schwartz, C. L., Krailo, M. D., Healey, J. H., Bernstein, M. L., Betcher, D., Ferguson, W. S., Gebhardt, M. C., Goorin, A. M., Harris, M., Kleinerman, E., Link, M. P., Nadel, H., Nieder, M., Siegal, G. P., Weiner, M. A., Wells, R. J., Womer, R. B., Grier, H. E. 2008; 26 (4): 633-638

  Abstract

  To compare three-drug chemotherapy with cisplatin, doxorubicin, and methotrexate with four-drug chemotherapy with cisplatin, doxorubicin, methotrexate, and ifosfamide for the treatment of osteosarcoma. To determine whether the addition of muramyl tripeptide (MTP) to chemotherapy enhances event-free survival (EFS) and overall survival in newly diagnosed patients with osteosarcoma.Six hundred sixty-two patients with osteosarcoma without clinically detectable metastatic disease and whose disease was considered resectable received one of four prospectively randomized treatments. All patients received identical cumulative doses of cisplatin, doxorubicin, and methotrexate and underwent definitive surgical resection of primary tumor. Patients were randomly assigned to receive or not to receive ifosfamide and/or MTP in a 2 x 2 factorial design. The primary end points for analysis were EFS and overall survival.In the current analysis, there was no evidence of interaction, and we were able to examine each intervention separately. The chemotherapy regimens resulted in similar EFS and overall survival. There was a trend toward better EFS with the addition of MTP (P = .08). The addition of MTP to chemotherapy improved 6-year overall survival from 70% to 78% (P = .03). The hazard ratio for overall survival with the addition of MTP was 0.71 (95% CI, 0.52 to 0.96).The addition of ifosfamide to cisplatin, doxorubicin, and methotrexate did not enhance EFS or overall survival for patients with osteosarcoma. The addition of MTP to chemotherapy resulted in a statistically significant improvement in overall survival and a trend toward better EFS.

  View details for DOI 10.1200/JCO.2008.14.0095

  View details for Web of Science ID 000254177400021

  View details for PubMedID 18235123

• Treatment of metastatuc Ewing Sarcoma/Primitive neuroectodermal tumor of bone: Evaluation of increasing the dose intensity of chemotherapy - A report from the children's oncology group PEDIATRIC BLOOD & CANCER Miser, J. S., Goldsby, R. E., Chen, Z., Krailo, M. D., Tarbell, N. J., Link, M. P., Fryer, C. J., Pritchard, D. J., Gebhardt, M. C., Dickman, P. S., Perlman, E. J., Meyers, P. A., Donaldson, S. S., Moore, S. G., Rausen, A. R., Vietti, T. J., Grier, H. E. 2007; 49 (7): 894-900

  Abstract

  The outcome for patients with Ewing sarcoma family of tumors (ESFTs) of bone with metastases at diagnosis remains poor despite new approaches to treatment. We evaluated whether a dose-intensity chemotherapy regimen improved survival for patients with ESFTs of bone with metastases at diagnosis.We entered 60 patients with metastatic ESFTs of bone onto a single arm trial of a new intensive therapy. Treatment consisted of 51-weeks of chemotherapy and local control of the primary with radiation, surgery, or both. The chemotherapeutic protocol included two alternating blocks: one with vincristine (2 mg/m(2)), doxorubicin (90 mg/m(2)), and cyclophosphamide (2,200 mg/m(2)); and the second with ifosfamide (2,800 mg/m(2)/day x 5 days) and etoposide (100 mg/m(2)/day x 5 days).Of the 60 patients with metastatic ESFTs of bone enrolled onto this single arm trial, 12 had metastasis to lung only, 7 to bone marrow or bone only, 38 to multiple sites, 2 in other sites and 3 not specified. There were three toxic deaths. Six patients (6-year cumulative incidence: 9%) developed second malignant neoplasms and died. The 6-year overall event-free survival (EFS) was 28% (standard error (SE) 6%) and survival (S) was 29% (SE 6%).An intensified treatment regimen using higher doses of cyclophosphamide, ifosfamide, and doxorubicin increased toxicity and risk of second malignancy without improving EFS and S.

  View details for DOI 10.1002/pbc.21233

  View details for Web of Science ID 000250487800004

  View details for PubMedID 17584910

• Final results of a prospective clinical trial with VAMP and low-dose involved-field radiation for children with low-risk Hodgkin's disease 47th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology Donaldson, S. S., Link, M. P., Weinstein, H. J., Rai, S. N., Brain, S., Billett, A. L., Hurwitz, C. A., Krasin, M., Kun, L. E., Marcus, K. C., Tarbell, N. J., Young, J. A., Hudson, M. M. AMER SOC CLINICAL ONCOLOGY. 2007: 332–37

  Abstract

  To evaluate outcome and assess complications in children and adolescents with low-risk Hodgkin's disease treated with vinblastine, doxorubicin, methotrexate, and prednisone (VAMP) chemotherapy and low-dose, involved-field radiation therapy (IFRT).One hundred ten children with low-risk Hodgkin's disease were treated with four cycles of VAMP and 15 Gy IFRT for those who achieved a complete response (CR) or 25.5 Gy for those with a partial response after two cycles of VAMP.With median follow-up of 9.6 years (range, 1.7 to 15.0), 5- and 10-year overall survival were 99.1% and 96.1%, respectively, and 5-and 10-year event-free survival (EFS) were 92.7% and 89.4%. Factors contributing to 10-year EFS were: early CR (P = .02), absence of B symptoms (P = .01), lymphocyte predominant histologic subtype (P = .04), and less than three initial sites of disease (P = .02). Organ toxicity has been limited to correctable hypothyroidism in 42% of irradiated patients, and one case of cardiac dysfunction. Seventeen healthy babies have been born to 106 survivors. There have been two malignant tumors: one thyroid cancer within the radiation therapy field and one Ewing's sarcoma outside the radiation therapy field.Risk-adapted, combined-modality therapy using VAMP chemotherapy with radiation is effective and well tolerated. Pediatric patients with low-risk Hodgkin's disease can be cured with therapy without an alkylating agent, bleomycin, etoposide, or high-dose, extended-field radiotherapy. Thus, these children are expected to retain normal fertility, organ function, and be at low risk of a second malignant tumor.

  View details for DOI 10.1200/JCO.2006.08.4772

  View details for Web of Science ID 000243729200016

  View details for PubMedID 17235049

• Therapy-related myelodysplasia and acute myeloid leukemia after Ewing sarcoma and primitive neuroectodermal tumor of bone: a report from the Children's Oncology Group BLOOD Bhatia, S., Krailo, M. D., Chen, Z., Burden, L., Askin, F. B., Dickman, P. S., Grier, H. E., Link, M. P., Meyers, P. A., Perlman, E. J., Rausen, A. R., Robison, L. L., Vietti, T. J., Miser, J. S. 2007; 109 (1): 46-51

  Abstract

  This study describes the magnitude of risk of therapy-related myelodysplasia and acute myeloid leukemia (t-MDS/AML) in 578 individuals diagnosed with Ewing sarcoma and enrolled on Children's Oncology Group therapeutic protocol, INT-0091. Between 1988 and 1992, patients with or without metastatic disease were randomized to receive doxorubicin, vincristine, cyclophosphamide, and dactinomycin (regimen A) or these 4 drugs alternating with etoposide and ifosfamide (regimen B). Between 1992 and 1994, patients with metastatic disease were nonrandomly assigned to receive high-intensity therapy (regimen C: regimen B therapy with higher doses of doxorubicin, cyclophosphamide, and ifosfamide). Median age at diagnosis of Ewing sarcoma was 12 years, and median length of follow-up, 8 years. Eleven patients developed t-MDS/AML, resulting in a cumulative incidence of 2% at 5 years. While patients treated on regimens A and B were at a low risk for development of t-MDS/AML (cumulative incidence: 0.4% and 0.9% at 5 years, respectively), patients treated on regimen C were at a 16-fold increased risk of developing t-MDS/AML (cumulative incidence: 11% at 5 years), when compared with those treated on regimen A. Increasing exposure to ifosfamide from 90 to 140 g/m2, cyclophosphamide from 9.6 to 17.6 g/m2, and doxorubicin from 375 to 450 mg/m2 increased the risk of t-MDS/AML significantly.

  View details for DOI 10.1182/blood-2006-01-023101

  View details for Web of Science ID 000243153900017

  View details for PubMedID 16985182

• A case of concurrent relapsed ALL and secondary AML 39th Biennial American Cytogenetics Conference Cherry, A. M., Bangs, C. D., Galperin, I., Atwater, S. K., Kuch, O., Link, M. P. KARGER. 2007

  View details for Web of Science ID 000245885400016

• Magnetic field exposure and prognostic factors in childhood leukemia BIOELECTROMAGNETICS Foliart, D. E., Mezei, G., Iriye, R., Silva, J. M., Ebi, K. L., Kheifets, L., Link, M. P., Kavet, R., Pollock, B. H. 2007; 28 (1): 69-71

  Abstract

  We examined the association between magnetic field (MF) exposure and the presence of prognostic risk factors among 482 children diagnosed with acute lymphoblastic leukemia (ALL) between 1996 and 2001. Personal 24-h MF measurements were obtained for 412 children; 386 children were included in analyses. There were no trends seen between increasing exposure to MF and the presence of adverse clinical and tumor-specific prognostic factors. Our results suggest that exposure to MF is not associated with the presence of unfavorable cytogenetic abnormalities in leukemic blast cells or with clinical factors at the time of diagnosis that predict poor survival.

  View details for DOI 10.1002/bem.20269

  View details for Web of Science ID 000242961700010

  View details for PubMedID 16988997

• Magnetic field exposure and long-term survival among children with leukaemia BRITISH JOURNAL OF CANCER Foliart, D. E., Pollock, B. H., Mezei, G., Iriye, R., Silva, J. M., Ebi, K. L., Kheifets, L., Link, M. P., Kavet, R. 2006; 94 (1): 161-164

  Abstract

  We examined the association between magnetic field (MF) exposure and survival among children with acute lymphoblastic leukaemia (ALL) treated at 51 Pediatric Oncology Group centres between 1996 and 2001. Of 1672 potentially eligible children under treatment, 482 (29%) participated and personal 24-h MF measurements were obtained from 412 participants. A total of 386 children with ALL and 361 with B-precursor ALL were included in the analysis of event-free survival (time from diagnosis to first treatment failure, relapse, secondary malignancy, or death) and overall survival. After adjustment for risk group and socioeconomic status, the event-free survival hazard ratio (HR) for children with measurements >/=0.3 muT was 1.9 (95% confidence interval (CI) 0.8, 4.9), compared to <0.1 muT. For survival, elevated HRs were found for children exposed to >/=0.3 muT (multivariate HR=4.5, 95% CI 1.5-13.8) but based on only four deaths among 19 children. While risk was increased among children with exposures above 0.3 muT, the small numbers limited inferences for this finding.

  View details for DOI 10.1038/sj.bjc.6602916

  View details for Web of Science ID 000234556100027

  View details for PubMedID 16404370

• Intensive therapy with growth factor support for patients with Ewing tumor metastatic at diagnosis: Pediatric oncology group/children's cancer group phase II study 9457 - A report from the children's oncology group JOURNAL OF CLINICAL ONCOLOGY Bernstein, M. L., Devidas, M., LaFreniere, D., Souid, A. K., Meyers, P. A., Gebhardt, M., Stine, K., Nicholas, R., Perlman, E. J., Dubowy, R., Wainer, I. W., Dickman, P. S., Link, M. P., Goorin, A., Grier, H. E. 2006; 24 (1): 152-159

  Abstract

  Prognosis is poor for Ewing sarcoma patients with metastasis at diagnosis. We intensified a five-drug therapy (ifosfamide, etoposide alternated with vincristine, doxorubicin, and cyclophosphamide) using filgrastim but not stem-cell support. We studied topotecan alone and combined with cyclophosphamide in therapeutic windows before the five-drug therapy. A randomly assigned proportion of patients received amifostine as a cytoprotective agent.Eligible patients were < or = 30 years old and had histologically proven Ewing sarcoma or primitive neuroectodermal tumor (PNET) and metastasis at diagnosis. Chemotherapeutic cycles began every 21 days, after recovery from toxicities.One hundred ten of the 117 patients enrolled were eligible. Thirty-six patients received initial topotecan. Three had partial responses (PRs), and 17 had progressive disease (PD). Thirty-seven patients were administered topotecan and cyclophosphamide; 21 of these patients achieved PR, and one patient had PD. In a randomly assigned group of 69 patients, amifostine did not provide myeloprotection, which was measured by absolute neutrophil count, platelet count, or cycle intervals. The best responses to the overall therapy included 45 complete responses, 41 PRs, stable disease in 14 patients, and PD in five patients. For all patients, the 2-year event-free survival (EFS) rate was 24% (+/- 4%), and the overall survival rate was 46% (+/- 5%). For the 39 patients with isolated pulmonary metastases, the 2-year EFS rate was 31% (+/- 7%) compared with 20% (+/- 5%) for patients with more widespread disease.Topotecan had limited activity in patients with Ewing sarcoma or PNET metastatic at diagnosis. The topotecan-cyclophosphamide combination was active. Amifostine was not myeloprotective. Overall results showed no improvement compared with previous studies.

  View details for DOI 10.1200/JCO.2005.02.1717

  View details for Web of Science ID 000234334700026

  View details for PubMedID 16382125

• Review of tonsillar lymphoma in pediatric patients from the Pediatric Oncology Group: What can be learned about some indications for microscopic examination? PEDIATRIC AND DEVELOPMENTAL PATHOLOGY Sayed, K., Savell, V. H., Hutchison, R. E., Kepner, J., Link, M. P., Schwenn, M., Mahmoud, H., Parham, D. M. 2005; 8 (5): 533-540

  Abstract

  Financial considerations have led to suggestions that routine microscopic evaluation of tonsils and adenoids is neither cost effective nor clinically indicated. However, the possibility of tonsillar lymphoma must be carefully weighed when making institutional policy decisions. One way to find an appropriate algorithm for pathologic examination is to examine the characteristics of biopsy-proved tonsillar lymphomas. To investigate the clinicopathologic characteristics of tonsillar lymphoma, we performed a retrospective analysis of patients who had non-Hodgkin lymphoma (NHL) and large-cell or Burkitt lymphoma involving the tonsils and adenoids and were registered on Pediatric Oncology Group (POG) protocols. Seventy-seven (9%) of 832 POG cases of NHL involved the tonsils and adenoids. Review of the pathology reports available from 29 of these cases revealed that NHL was incidentally discovered by pathologic examination in only 5 cases, all of which had clinical evidence of unilateral tonsillar enlargement or size discrepancy by gross examination. The other 24 cases indicated a clinical suspicion of tonsillar cancer, as judged by a preoperative diagnosis or by a request for frozen-section examination. We conclude that in most cases there is a clinical suspicion of tonsillar NHL at the time of gross examination. With routine cases, we predict that the use of comparative organ weights, a clinical impression of tonsillar asymmetry, and review of clinical history will increase the recognition of tonsillar lymphoma when "gross-only" protocols are employed for specimen handling.

  View details for DOI 10.1007/s10024-005-0043-6

  View details for Web of Science ID 000233324800003

  View details for PubMedID 16211449

• Osteosarcoma: A randomized, prospective trial of the addition of ifosfamide and/or muramyl tripeptide to cisplatin, doxorubicin, and high-dose methotrexate JOURNAL OF CLINICAL ONCOLOGY Meyers, P. A., Schwartz, C. L., Krailo, M., Kleinerman, E. S., Betcher, D., Bernstein, M. L., Conrad, E., Ferguson, W., Gebhardt, M., Goorin, A. M., Harris, M. B., Healey, J., Huvos, A., Link, M., Montebello, J., Nadel, H., Nieder, M., Sato, J., Siegal, G., Weiner, M., Wells, R., Wold, L., Womer, R., Grier, H. 2005; 23 (9): 2004-2011

  Abstract

  To determine whether the addition of ifosfamide and/or muramyl tripeptide (MTP) encapsulated in liposomes to cisplatin, doxorubicin, and high-dose methotrexate (HDMTX) could improve the probability for event-free survival (EFS) in newly diagnosed patients with osteosarcoma (OS).Six hundred seventy-seven patients with OS without clinically detectable metastatic disease were treated with one of four prospectively randomized treatments. All patients received identical cumulative doses of cisplatin, doxorubicin, and HDMTX and underwent definitive surgical resection of the primary tumor. Patients were randomly assigned to receive or not to receive ifosfamide and/or MTP in a 2 double dagger 2 factorial design. The primary end point for analysis was EFS.Patients treated with the standard arm of therapy had a 3-year EFS of 71%. We could not analyze the results by factorial design because we observed an interaction between the addition of ifosfamide and the addition of MTP. The addition of MTP to standard chemotherapy achieved a 3-year EFS rate of 68%. The addition of ifosfamide to standard chemotherapy achieved a 3-year EFS rate of 61%. The addition of both ifosfamide and MTP resulted in a 3-year EFS rate of 78%.The addition of ifosfamide in this dose schedule to standard chemotherapy did not enhance EFS. The addition of MTP to chemotherapy might improve EFS, but additional clinical and laboratory investigation will be necessary to explain the interaction between ifosfamide and MTP.

  View details for DOI 10.1200/JCO.2005.06.031

  View details for Web of Science ID 000228024800028

  View details for PubMedID 15774791

• Epstein-Barr virus-associated peripheral T-cell lymphoma and hemophagocytic syndrome arising after liver transplantation: Case report and review of the literature PEDIATRIC BLOOD & CANCER George, T. I., Jeng, M., Berquist, W., Cherry, A. M., Link, M. P., Arber, D. A. 2005; 44 (3): 270-276

  Abstract

  Post-transplantation lymphoproliferative disorders (PTLD) are a well-recognized complication of solid organ transplantation. The vast majority of PTLD are Epstein-Barr virus (EBV)-related infections that manifest as B-cell malignancies. We report an unusual case of an EBV-associated T-cell lymphoma in a 10-year-old boy who had previously undergone liver transplantation at age 4 years. He presented with hemophagocytic syndrome (HPS) and active EBV infection, with positive serum titers and polymerase chain reaction (PCR) for EBV in blood, colon, and antral samples.

  View details for DOI 10.1002/pbc.20231

  View details for Web of Science ID 000226798300015

  View details for PubMedID 15468305

• High-dose therapy and autologous hematopoietic stem-cell transplantation for recurrent or refractory pediatric Hodgkin's disease: Results and prognostic indices 45th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology (ASTRO) Lieskovsky, Y. E., Donaldson, S. S., Torres, M. A., Wong, R. M., Amylon, M. D., Link, M. P., Agarwal, R. AMER SOC CLINICAL ONCOLOGY. 2004: 4532–40

  Abstract

  To evaluate the outcome of pediatric patients with refractory or relapsed Hodgkin's disease (HD) who undergo high-dose therapy and autologous hematopoietic stem-cell transplantation (AHSCT).From 1989 to 2001, 41 pediatric patients with relapsed or primary refractory HD underwent high-dose therapy followed by AHSCT according to one of four autologous transplantation protocols at Stanford University Medical Center (Stanford, CA). Pretreatment factors were analyzed by univariate and multivariate analysis for prognostic significance for 5-year overall survival (OS), event-free survival (EFS), and progression-free survival (PFS).At a median follow-up of 4.2 years (range, 0.7 to 11.9 years), the 5-year OS, EFS, and PFS rates were 68%, 53%, and 63%, respectively. Multivariate analysis determined the following three factors to be significant predictors of poor OS and EFS: extranodal disease at first relapse, presence of mediastinal mass at time of AHSCT, and primary induction failure. Two of these factors also predicted for poor PFS (extranodal disease at time of first relapse and presence of mediastinal mass at time of transplantation).More than half of children with relapsed or refractory HD can be successfully treated with the combination of high-dose therapy and AHSCT, confirming the efficacy of this approach. Further investigation is now required to determine the optimal timing of AHSCT, as well as to develop alternative regimens for those patients with factors prognostic for poor outcome after AHSCT.

  View details for DOI 10.1200/JCO.2004.02.121

  View details for Web of Science ID 000225175600015

  View details for PubMedID 15542804

• Risk-adapted, combined-modality therapy with VAMP/COP and response-based, involved-field radiation for unfavorable pediatric Hodgkin's disease JOURNAL OF CLINICAL ONCOLOGY Hudson, M. M., Krasin, M., Link, M. P., Donaldson, S. S., BILLUPS, C., Merchant, T. E., Kun, L., Billet, A. L., Kaste, S., Tarbell, N. J., Howard, S., Friedmann, A. M., Hurwitz, C. A., Young, J. A., Marcus, K. C., Rai, S., Cowan, T., Weinstein, H. J. 2004; 22 (22): 4541-4550

  Abstract

  To evaluate the efficacy of vinblastine, doxorubicin, methotrexate, and prednisone (VAMP) and cyclophosphamide, vincristine, and procarbazine (COP) chemotherapy and response-based, involved-field radiation, a combined-modality regimen that limits doses of alkylating agents, anthracyclines, and radiation, in children with advanced and unfavorable Hodgkin's disease.From 1993 to 2000, 159 children and adolescents with unfavorable Hodgkin's disease received three alternating cycles (total of six cycles) of VAMP/COP chemotherapy followed by response-based, involved-field radiation therapy: 15 Gy was administered to patients achieving a complete response, and 25.5 Gy was administered to those achieving a partial response after the first two cycles of chemotherapy and to all sites of bulky lymphadenopathy. Unfavorable disease was defined as clinical stage I and II with bulky peripheral nodal disease greater than 6 cm, initial bulky mediastinal mass 33% or more of the intrathoracic diameter, and/or "B" symptoms and all stage III and IV.Study enrollment was closed after an interim analysis estimated a 5-year event-free survival (EFS) rate below a predefined level. Disease presentation was localized (stage I/II) in 77 patients (48.4%) and advanced (stage III/IV) in 82 patients (51.6%). At a median follow-up of 5.8 years (range, 1.3 to 10.0 years), 38 patients had events, including relapse/progression (n = 35), second malignancy (n = 2), and accidental death (n = 1); nine relapses (25.7%) occurred greater than 4 years from diagnosis. Five-year survival and EFS estimates are 92.7% +/- 2.5% and 75.6% +/- 4.1%, respectively.Risk-adapted combined-modality therapy with VAMP/COP and response-based, involved-field radiation therapy results in an unsatisfactory outcome for pediatric patients with unfavorable presentations of Hodgkin's disease.

  View details for DOI 10.1200/JCO.2004.02.139

  View details for Web of Science ID 000225175600016

  View details for PubMedID 15542805

• Cyclophosphamide dose intensification during induction therapy for intermediate-risk pediatric rhabdomyosarcoma is feasible but does not improve outcome: A report from the soft tissue sarcoma committee of the children's oncology group 38th Annual Meeting of the American-Society-of-Clinical-Oncology Spunt, S. L., Smith, L. M., Ruymann, F. B., Qualman, S. J., Donaldson, S. S., Rodeberg, D. A., Anderson, J. R., Crist, W. M., Link, M. P. AMER ASSOC CANCER RESEARCH. 2004: 6072–79

  Abstract

  More than half of pediatric rhabdomyosarcoma cases have intermediate-risk features and suboptimal outcome (3-year failure-free survival estimates, 55 to 76%). Dose intensification of known active agents may improve outcome.This pilot study evaluated the feasibility of dose intensification of cyclophosphamide in previously untreated patients ages < 21 years with intermediate-risk rhabdomyosarcoma. Induction therapy comprised four 3-week cycles of VAC: vincristine (V) 1.5 mg/m2 on days 0, 7, and 14; actinomycin D (A) 1.35 mg/m2 on day 0; and dose-intensified cyclophosphamide (C) on days 0, 1, and 2. The three cyclophosphamide dose levels tested were as follows: (a) 1.2 g/m2/dose; (b) 1.5 g/m2/dose; and (c) 1.8 g/m2/dose. Continuation therapy comprised nine additional cycles of VAC with 2.2 g/m2/cycle of C. Radiotherapy was administered at week 0 (parameningeal tumors with intracranial extension) or week 12 or 15 (all others).Between October 1996 and August 1999, 115 eligible patients were enrolled. Three of 15 patients treated at dose level 2 experienced life-threatening dose-limiting toxicity (typhlitis +/- other severe toxicity). Dose level 1 was the maximum-tolerated dose, and 91 evaluable patients were treated at this level. The 3-year failure-free and overall survival estimates for patients treated at the maximum-tolerated dose were 52% (95% confidence interval, 41-64%) and 67% (95% confidence interval, 56-77%), respectively, at a median follow-up of 3 years.A 64% increase in the standard cyclophosphamide dosage during induction (to 3.6 g/m2/cycle) was tolerated. However, outcomes were similar to those observed at lower dosages, suggesting that alkylator dose intensification does not benefit patients with intermediate-risk rhabdomyosarcoma.

  View details for Web of Science ID 000224080200014

  View details for PubMedID 15447992

• Treatment of metastatic Ewing's sarcoma or primitive neuroectodermal tumor of bone: Evaluation of combination ifosfamide and etoposide - A children's cancer group and pediatric oncology group study JOURNAL OF CLINICAL ONCOLOGY Miser, J. S., Krailo, M. D., Tarbell, N. J., Link, M. P., Fryer, C. J., Pritchard, D. J., Gebhardt, M. C., Dickman, P. S., Perlman, E. J., Meyers, P. A., Donaldson, S. S., Moore, S., Rausen, A. R., Vietti, T. J., Grier, H. E. 2004; 22 (14): 2873-2876

  Abstract

  One hundred twenty patients with metastatic Ewing's sarcoma or primitive neuroectodermal tumor (PNET) of bone were entered onto a randomized trial evaluating whether the addition of ifosfamide and etoposide to vincristine, doxorubicin, cyclophosphamide, and dactinomycin improved outcomes.Thirty-two patients had metastases to lungs only, 12 patients had metastases to bone marrow or bones only, 64 patients had metastases in multiple sites, and five patients had metastases in other sites; seven patients could not be assessed precisely. Treatment comprised 9 weeks of chemotherapy before local control and 42 weeks of chemotherapy; thereafter, regimen A consisted of vincristine 2 mg/m(2), cyclophosphamide 1,200 mg/m(2), and either doxorubicin 75 mg/m(2) or dactinomycin 1.25 mg/m(2). Regimen B consisted of regimen A alternating every 3 weeks with ifosfamide 1,800 mg/m(2)/d for 5 days and etoposide 100 mg/m(2)/d for 5 days.Patients treated on regimen B did not have significantly better survival than those treated on regimen A. The event-free survival (EFS) and survival (S) at 8 years were 20% (SE, 5%) and 32% (SE, 6%), respectively, for those treated on regimen A and 20% (SE, 6%) and 29% (SE, 6%), respectively, for those treated on regimen B. Patients who had only lung metastases had EFS and S of 32% (SE, 8%) and 41% (SE, 9%), respectively, at 8 years. There were six toxic deaths (5%), four from cardiac toxicity and two from sepsis (four treated on regimen B and two treated on regimen A). Two had second malignant neoplasms.Adding ifosfamide and etoposide to standard therapy does not improve outcomes of patients with Ewing's sarcoma or PNET of bone with metastases at diagnosis.

  View details for DOI 10.1200/JCO.2004.01.041

  View details for Web of Science ID 000222729000017

  View details for PubMedID 15254055

• High-dose methotrexate pharmacokinetics and outcome of children and young adults with osteosarcoma CANCER Crews, K. R., Liu, T., Rodriguez-Galindo, C., Tan, M., Meyer, W. H., Panetta, J. C., Link, M. P., Daw, N. C. 2004; 100 (8): 1724-1733

  Abstract

  High-dose methotrexate (HDMTX) is used frequently in combination regimens that include nephrotoxic chemotherapy. The authors evaluated the impact of factors such as age and prior nephrotoxic agents on MTX pharmacokinetics in children and young adults with osteosarcoma and examined whether MTX pharmacokinetic parameters were associated with outcome.The authors evaluated MTX pharmacokinetics in 140 patients who were treated with 1083 courses of HDMTX on 3 consecutive studies of multiagent chemotherapy at a single institution. The influence of MTX pharmacokinetics on the outcome of 107 patients with localized disease was examined.Mean peak MTX concentrations > or = 1000 microM were achieved in 135 patients (96%). MTX clearance was decreased after cisplatin therapy (P = 0.01), after cisplatin in combination with ifosfamide therapy (P < 0.0001), and after MTX therapy (P = 0.003). In patients with localized osteosarcoma, a higher mean MTX area under the curve, a higher mean peak concentration of MTX, a longer mean time above a threshold concentration (500 microM), and a lower mean MTX clearance were associated with lower probability of event-free survival (EFS). Patients who had a mean peak MTX plasma concentration > 1500 microM were found to have a worse outcome (estimated 5-year EFS, 58.5% +/- 6.7%) compared with patients who had a mean peak concentration < or = 1500 microM (estimated 5-year EFS, 75.5% +/- 6.6%; P = 0.02).When HDMTX (12 g/m(2)) was used with multiagent therapy for patients with osteosarcoma, very high MTX exposures were associated with poorer outcome. The prospective evaluation of MTX pharmacokinetics and their relation to outcome in a large study is warranted to further substantiate the current findings and to elucidate the causative mechanism.

  View details for DOI 10.1002/cncr.20152

  View details for Web of Science ID 000220725400024

  View details for PubMedID 15073863

• National Institutes of Health State-of-the-Science Conference Statement: Symptom management in cancer: pain, depression, and fatigue, July 15-17, 2002. Journal of the National Cancer Institute. Monographs Patrick, D. L., Ferketich, S. L., Frame, P. S., Harris, J. J., Hendricks, C. B., Levin, B., Link, M. P., Lustig, C., McLaughlin, J., Reid, L. D., Turrisi, A. T., Unützer, J., Vernon, S. W. 2004: 9-16

  Abstract

  Despite advances in early detection and effective treatment, cancer remains one of the most feared diseases. Among the most common side effects of cancer and treatments for cancer are pain, depression, and fatigue. Although research is producing increasingly hopeful insights into the causes and cures for cancer, efforts to manage the side effects of the disease and its treatments have not kept pace. The challenge that faces us is how to increase awareness of the importance of recognizing and actively addressing cancer-related distress. The National Institutes of Health (NIH) convened a State-of-the-Science Conference on Symptom Management in Cancer: Pain, Depression, and Fatigue to examine the current state of knowledge regarding the management of pain, depression, and fatigue in individuals with cancer and to identify directions for future research. Specifically, the conference examined how to identify individuals who are at risk for cancer-related pain, depression, and/or fatigue; what treatments work best to address these symptoms when they occur; and what is the best way to deliver interventions across the continuum of care. STATE-OF-THE-SCIENCE PROCESS: A non-advocate, non-Federal, 14-member panel of experts representing the fields of oncology, radiology, psychology, nursing, public health, social work, and epidemiology prepared the statement. In addition, 24 experts in medical oncology, geriatrics, pharmacology, psychology, and neurology presented data to the panel and to the conference audience during the first 1.5 days of the conference. The panel then prepared its statement, addressing the five predetermined questions and drawing on submitted literature, the speakers' presentations, and discussions held at the conference. The statement was presented to the conference audience, followed by a press conference to allow the panel to respond to questions from the media. After its release at the conference, the draft statement was made available on the Internet. The panel's final statement is available at http://consensus.nih.gov.The panel concluded that the available evidence supports a variety of interventions for treating cancer patients' pain, depression, and fatigue. Clinicians should routinely use brief assessment tools to ask patients about pain, depression, and fatigue and to initiate evidence-based treatments. Assessment should include discussion about common symptoms experienced by cancer patients, and these discussions should continue over the duration of the illness. Impediments to effective symptom management in cancer patients can arise from different sources and interactions among providers, patients and their families, and the health care system. Numerous factors could interfere with adequate symptom management. Among these factors are incomplete effectiveness of some treatments, a lack of sufficient knowledge regarding effective treatment strategies, patient reluctance to report symptoms to caregivers, a belief that such symptoms are simply a part of the cancer experience that must be tolerated, and inadequate coverage and reimbursement for some treatments. Additional research is needed on the definition, occurrence, the treatment of pain, depression, and fatigue, alone and in combination, in adequately funded prospective studies. The panel also concluded that the state of the science in cancer symptom management should be reassessed periodically.

  View details for PubMedID 15263035

• National Institutes of Health State-of-the-Science Conference Statement: Symptom Management in Cancer: Pain, Depression, and Fatigue, July 15-17, 2002. Journal of the National Cancer Institute Patrick, D. L., Ferketich, S. L., Frame, P. S., Harris, J. J., Hendricks, C. B., Levin, B., Link, M. P., Lustig, C., McLaughlin, J., Ried, L. D., Turrisi, A. T., Unützer, J., Vernon, S. W. 2003; 95 (15): 1110-1117

  Abstract

  Despite advances in early detection and effective treatment, cancer remains one of the most feared diseases. Among the most common side effects of cancer and treatments for cancer are pain, depression, and fatigue. Although research is producing increasingly hopeful insights into the causes and cures for cancer, efforts to manage the side effects of the disease and its treatments have not kept pace. The challenge that faces us is how to increase awareness of the importance of recognizing and actively addressing cancer-related distress. The National Institutes of Health (NIH) convened a State-of-the-Science Conference on Symptom Management in Cancer: Pain, Depression, and Fatigue to examine the current state of knowledge regarding the management of pain, depression, and fatigue in individuals with cancer and to identify directions for future research. Specifically, the conference examined how to identify individuals who are at risk for cancer-related pain, depression, and/or fatigue; what treatments work best to address these symptoms when they occur; and what is the best way to deliver interventions across the continuum of care. State-of-the-Science Process: A non-advocate, non-Federal, 14-member panel of experts representing the fields of oncology, radiology, psychology, nursing, public health, social work, and epidemiology prepared the statement. In addition, 24 experts in medical oncology, geriatrics, pharmacology, psychology, and neurology presented data to the panel and to the conference audience during the first 1.5 days of the conference. The panel then prepared its statement, addressing the five predetermined questions and drawing on submitted literature, the speakers' presentations, and discussions held at the conference. The statement was presented to the conference audience, followed by a press conference to allow the panel to respond to questions from the media. After its release at the conference, the draft statement was made available on the Internet. The panel's final statement is available at http://consensus.nih.gov.The panel concluded that the available evidence supports a variety of interventions for treating cancer patients' pain, depression, and fatigue. Clinicians should routinely use brief assessment tools to ask patients about pain, depression, and fatigue and to initiate evidence-based treatments. Assessment should include discussion about common symptoms experienced by cancer patients, and these discussions should continue over the duration of the illness. Impediments to effective symptom management in cancer patients can arise from different sources and interactions among providers, patients and their families, and the health care system. Numerous factors could interfere with adequate symptom management. Among these factors are incomplete effectiveness of some treatments, a lack of sufficient knowledge regarding effective treatment strategies, patient reluctance to report symptoms to caregivers, a belief that such symptoms are simply a part of the cancer experience that must be tolerated, and inadequate coverage and reimbursement for some treatments. Additional research is needed on the definition, occurrence, the treatment of pain, depression, and fatigue, alone and in combination, in adequately funded prospective studies. The panel also concluded that the state of the science in cancer symptom management should be reassessed periodically.

  View details for PubMedID 12902440

• Prognostic factors for children with Hodgkin's disease treated with combined-modality therapy JOURNAL OF CLINICAL ONCOLOGY Smith, R. S., Chen, G., Hudson, M. M., Link, M. P., Kun, L., Weinstein, H., Billett, A., Marcus, K. J., Tarbell, N. J., Donaldson, S. S. 2003; 21 (10): 2026-2033

  Abstract

  Evaluation of pretreatment factors to identify children at high risk for relapse after combined-modality therapy for Hodgkin's disease.From 1990 to 2000, 328 pediatric patients with clinical stage I to IV Hodgkin's disease were treated with chemotherapy and low-dose involved-field radiotherapy on prospective, collaborative, risk-adapted protocols at three institutions. Pretreatment factors were analyzed by univariate and multivariate analysis for prognostic significance for 5-year disease-free survival (DFS) and overall survival (OS).With a median follow-up of 59 months (range, 8 to 125 months), the 5-year DFS and OS for all patients were 83% and 93%, respectively. Several factors were associated with inferior DFS and OS by univariate analysis. By multivariate analysis, male sex; stage IIB, IIIB, or IV disease; bulky mediastinal disease; WBC more than 13.5 x 10(3)/mm3; and hemoglobin less than 11.0 g/dL were significant for inferior DFS. A prognostic index was developed incorporating the five significant factors from the multivariate analysis, assigning each a score of 1. The 5-year DFS and OS for children with a prognostic score of 0 to 1 were 94% and 99%; score 2, 85% and 96%; score 3, 71% and 92%; and score 4 or 5, 49% and 72%, respectively. There was a significant difference in DFS among each of these groups, with significantly worse OS in those with a score of 4 to 5.A prognostic index that was based on five pretreatment factors correlated with inferior DFS by multivariate analysis stratified patients by outcome; this may be useful in assigning children with Hodgkin's disease to risk-adapted therapy.

  View details for DOI 10.1200/JCO.2003.07.12.4

  View details for Web of Science ID 000182903400018

  View details for PubMedID 12743158

• Presurgical chemotherapy compared with immediate surgery and adjuvant chemotherapy for nonmetastatic osteosarcoma: Pediatric oncology group study POG-8651 JOURNAL OF CLINICAL ONCOLOGY Goorin, A. M., Schwartzentruber, D. J., Devidas, M., Gebhardt, M. C., AYALA, A. G., Harris, M. B., Helman, L. J., Grier, H. E., Link, M. P. 2003; 21 (8): 1574-1580

  Abstract

  Successful therapeutic interventions to prevent disease progression in patients with nonmetastatic osteosarcoma have included surgery with adjuvant chemotherapy. Presurgical chemotherapy has been advocated for these patients because of putative improvement in event-free survival (EFS). The advantages of presurgical chemotherapy include early administration of systemic chemotherapy, shrinkage of primary tumor, and pathologic identification of risk groups. The theoretic disadvantage is that it exposes a large tumor burden to marginally effective chemotherapy. The contribution of chemotherapy and surgery timing has not been tested rigorously.Between 1986 and 1993, we conducted a prospective trial in patients with nonmetastatic osteosarcoma who were assigned randomly to immediate surgery or presurgical chemotherapy. Except for the timing of surgery (week 0 or 10), patients received 44 weeks of identical combination chemotherapy that included high-dose methotrexate with leucovorin rescue, doxorubicin, cisplatin, bleomycin, cyclophosphamide, and dactinomycin.One hundred six patients were enrolled onto this study. Six were excluded from analysis. Of the remaining 100 patients, 45 were randomly assigned to immediate chemotherapy, and 55 were randomly assigned to immediate surgery. Sixty-seven patients remain disease-free. At 5 years, the projected EFS +/- SE is 65% +/- 6% (69% +/- 8% for immediate surgery and 61% +/- 8% for presurgical chemotherapy; P =.8). The treatment arms had similar incidence of limb salvage (55% for immediate surgery and 50% for presurgical chemotherapy).Chemotherapy was effective in both treatment groups. There was no advantage in EFS for patients given presurgical chemotherapy.

  View details for DOI 10.1200/JCO.2003.08.165

  View details for Web of Science ID 000182300200023

  View details for PubMedID 12697883

• Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone NEW ENGLAND JOURNAL OF MEDICINE Grier, H. E., Krailo, M. D., Tarbell, N. J., Link, M. P., Fryer, C. J., Pritchard, D. J., Gebhardt, M. C., Dickman, P. S., Perlman, E. J., Meyers, P. A., Donaldson, S. S., Moore, S., Rausen, A. R., Vietti, T. J., Miser, J. S. 2003; 348 (8): 694-701

  Abstract

  Ewing's sarcoma and primitive neuroectodermal tumor of bone are closely related, highly malignant tumors of children, adolescents, and young adults. A new drug combination, ifosfamide and etoposide, was highly effective in patients with Ewing's sarcoma or primitive neuroectodermal tumor of bone who had a relapse after standard therapy. We designed a study to test whether the addition of these drugs to a standard regimen would improve the survival of patients with newly diagnosed disease.Patients 30 years old or younger with Ewing's sarcoma, primitive neuroectodermal tumor of bone, or primitive sarcoma of bone were eligible. The patients were randomly assigned to receive 49 weeks of standard chemotherapy with doxorubicin, vincristine, cyclophosphamide, and dactinomycin or experimental therapy with these four drugs alternating with courses of ifosfamide and etoposide.A total of 518 patients met the eligibility requirements. Of 120 patients with metastatic disease, 62 were randomly assigned to the standard-therapy group and 58 to the experimental-therapy group. There was no significant difference in five-year event-free survival between the treatment groups (P=0.81). Among the 398 patients with nonmetastatic disease, the mean (+/-SE) five-year event-free survival among the 198 patients in the experimental-therapy group was 69+/-3 percent, as compared with 54+/-4 percent among the 200 patients in the standard-therapy group (P=0.005). Overall survival was also significantly better among patients in the experimental-therapy group (72+/-3.4 percent vs. 61+/-3.6 percent in the standard-therapy group, P=0.01).The addition of ifosfamide and etoposide to a standard regimen does not affect the outcome for patients with metastatic disease, but it significantly improves the outcome for patients with nonmetastatic Ewing's sarcoma, primitive neuroectodermal tumor of bone, or primitive sarcoma of bone.

  View details for Web of Science ID 000181014400004

  View details for PubMedID 12594313

• Prognostic factors and clinical outcomes in children and adolescents with metastatic rhabdomyosarcoma - A report from the intergroup rhabdomyosarcoma study IV JOURNAL OF CLINICAL ONCOLOGY Breneman, J. C., Lyden, E., Pappo, A. S., Link, M. P., Anderson, J. R., Parham, D. M., Qualman, S. J., Wharam, M. D., Donaldson, S. S., Maurer, H. M., Meyer, W. H., Baker, K. S., Paidas, C. N., Crist, W. M. 2003; 21 (1): 78-84

  Abstract

  To identify risk factors associated with outcomes in children with metastatic rhabdomyosarcoma (RMS) treated on the fourth Intergroup Rhabdomyosarcoma Study (IRS-IV).Patients with metastatic RMS were treated with one of two regimens that incorporated a window of either ifosfamide and etoposide (IE) with vincristine, dactinomycin, and cyclophosphamide (VAC) or vincristine, melphalan (VM) and VAC. Study end points were failure-free survival (FFS) and overall survival (OS). Clinical factors including age, histology, sites of primary and metastatic disease, and number of sites of metastatic disease were correlated with those end points.One hundred twenty-seven patients were eligible for analysis. The estimated 3-year OS and FFS for all patients were 39% and 25%, respectively. By univariate analysis, 3-year OS was significantly influenced by histology (47% for embryonal v 34% for all others, P =.026) and increasing number of metastatic sites (P =.028). By multivariate analysis, the presence of two or fewer metastatic sites was the only significant predictor (P =.007 and.006, respectively). The combination of embryonal histology with two or fewer metastatic sites identified a subgroup with 3-year FFS of 40% and OS of 47%.Children with group IV RMS treated on the IRS-IV study had improved OS and FFS if they had two or fewer metastatic sites and embryonal histology. This favorable subset of patients has outcomes approaching those observed in selected patients with localized, nonmetastatic disease. Thus, these patients might not be appropriate candidates for regimens that include experimental agents with substantial toxicities or unproven antitumor activity.

  View details for Web of Science ID 000183281100014

  View details for PubMedID 12506174

• Children from ethnic minorities have benefited equally as other children from contemporary therapy for rhabdomyosarcoma: A report from the intergroup rhabdomyosarcoma study group JOURNAL OF CLINICAL ONCOLOGY Baker, K. S., Anderson, J. R., Lobe, T. E., Wharam, M. D., Qualman, S. J., Raney, R. B., Ruymann, F. B., Womer, R. B., Meyer, W. H., Link, M. P., Crist, W. M. 2002; 20 (22): 4428-4433

  Abstract

  To define the clinical characteristics of rhabdomyosarcoma (RMS) occurring in children from ethnic minorities and determine whether these children have benefited equally from advances in therapy.This was a retrospective cohort analysis of children treated on the Intergroup Rhabdomyosarcoma Study Group protocols between 1984 and 1997. The clinical features and outcomes of 336 African-American children and 286 children from other ethnic minorities were compared with those of white children (n = 1,721).African-American, other ethnic group, and white children enjoyed similar 5-year failure-free survivals (FFS) of 61%, 61%, and 66%, respectively, P =.15. Compared with white children, nonwhite patients more often had (1) invasive, T2 tumors (P =.03); (2) stage 2 or 3 tumors (P =.003); (3) large tumors (more than 5 cm, P <.006); and/or (4) tumors with positive regional nodes (ie, N1, P =.002). Using Cox proportional hazards analysis, seven patient risk categories were defined with significant differences in outcome. This model was then used to search for other factors associated with FFS after adjusting for these risk categories. Only T stage and age remained associated with FFS (P =.001 and P <.001, respectively). After adjusting for T stage, risk category, and age, we explored the relationship of ethnic group to FFS and found that, compared with whites, the relative risk of failure was 1.14 for African-American patients and 1.2 for other ethnic minority patients, values that are not significantly different.Patients from ethnic minority groups more often have larger, invasive tumors with positive lymph nodes. Nevertheless, they have benefited as equally as white children from the dramatic progress in therapy of RMS.

  View details for DOI 10.1200/JCO.2002.11.131

  View details for Web of Science ID 000179267200004

  View details for PubMedID 12431964

• National action plan for childhood cancer: report of the national summit meetings on childhood cancer. CA: a cancer journal for clinicians Arceci, R., Ettinger, A., Forman, E., Haase, G. M., Hammond, G. D., Hoffman, R., Kupst, M. J., Link, M. P., Lustig, C. P., Traynor, D. S. 2002; 52 (6): 377-379

  View details for PubMedID 12469766

• Assessment of lymphadenopathy in children PEDIATRIC CLINICS OF NORTH AMERICA Twist, C. J., Link, M. P. 2002; 49 (5): 1009-?

  Abstract

  The assessment of lymphadenopathy in children is a common diagnostic problem in pediatrics. An understanding of the wide variety of diseases and conditions that may present as lymphadenopathy is essential to determining the most appropriate work up for an individual patient. Although the majority of these children will prove to have a benign disorder, it is important that the pediatrician also have an appreciation for the malignant diseases that may present with lymphadenopathy, so that in such cases the diagnosis of a serious or life-threatening disease can be made in a timely manner.

  View details for Web of Science ID 000178952200008

  View details for PubMedID 12430623

• Minimax two-stage-designs with applications to tissue banking case-control studies STATISTICS IN MEDICINE Shuster, J., Link, M., Camitta, B., Pullen, J., Behm, F. 2002; 21 (17): 2479-2493

  Abstract

  'Tissue banks' are created, at least in part, to help medical scientists learn about disease biology on the basis of samples provided by patients on treatment protocols that were competed years earlier. The bank inventory consists of precious non-renewable patient material (such as frozen diagnostic blood or bone marrow), which can be linked to both clinical data and long term follow-up information. Case-control studies, where cases represent clinical failures and controls clinical successes, are ideal for rapidly learning if a laboratory marker might have prognostic significance. While group sequential (multi-stage) methods are widely used in clinical trials, they have rarely been applied in case-control studies. Further, unlike clinical trials where safety and efficiency may actually be in conflict, case-control studies can focus on efficiency. Hence, minimizing the expected sample size is a desirable goal in such a setting. Since the true effect size is never known, and since no prior distribution can be postulated for the effect size, we have opted for the minimax solution. A strategy is developed to determine amongst all two-stage designs with given type I and type II errors, the one for which the maximum expected sample size is minimized. The user is provided with simple tables, whereby one can determine everything necessary to conduct the study from the corresponding calculation for a single-stage design. A matched pair example is given where the suggested design can be modified, to obtain a superior 'two-plus' stage design. The basic idea is to conduct the first stage as planned, but use the estimate of variance to redesign the study, without using the estimate of effect size in the redesign.

  View details for DOI 10.1002/sim.1198

  View details for Web of Science ID 000177673100003

  View details for PubMedID 12205694

• Treatment of unfavorable childhood Hodgkin's disease with VEPA and low-dose, involved-field radiation JOURNAL OF CLINICAL ONCOLOGY Friedmann, A. M., Hudson, M. M., Weinstein, H. J., Donaldson, S. S., Kun, L., Tarbell, N. J., Link, M. P. 2002; 20 (14): 3088-3094

  Abstract

  Between January 1990 and April 1993, 56 pediatric patients with Hodgkin's disease were treated on a single-arm trial at three institutions with a regimen designed to maintain high cure rates while minimizing the potential late effects of treatment, such as infertility, second malignant neoplasms, and cardiopulmonary injury.The regimen used combined-modality therapy with six cycles of vinblastine, etoposide, prednisone, and doxorubicin (VEPA) chemotherapy and low-dose, involved-field radiation. Unfavorable features comprised bulky presentations of localized (stage I or II) disease or advanced (stage III or IV) Hodgkin's disease.Of 56 patients enrolled, 26 (46%) had unfavorable presentations of stage I/II disease and 30 (54%) had advanced (stage III/IV) disease. Seventy-nine percent of the patients are alive without disease at a median follow-up time of 8.9 years from diagnosis. Nineteen patients had events at a median of 1.5 years (range, 0.4 to 7.9 years) from diagnosis; 17 patients relapsed, one died of cardiomyopathy, and one died of accidental injuries. Survival and event-free survival (EFS) estimates at 5 years for the entire cohort were 81.9% (SE, 5.2%) and 67.8% (SE, 6.3%), respectively. Five-year EFS by stage was 100% for stage I, 79.2% (SE, 8.3%) for stage II, 70% (SE, 14.5%) for stage III, and 49.5% (SE, 11.3%) for stage IV patients.Combined-modality therapy with VEPA chemotherapy and low-dose, involved-field radiation is adequate for disease control of early-stage patients with unfavorable features, but it is inferior to other standard regimens for advanced-stage patients.

  View details for DOI 10.1200/JCO.2002.03.051

  View details for Web of Science ID 000176920000008

  View details for PubMedID 12118022

• VAMP and low-dose, involved-field radiation for children and adolescents with favorable, early-stage Hodgkin's disease: Results of a prospective clinical trial JOURNAL OF CLINICAL ONCOLOGY Donaldson, S. S., Hudson, M. M., Lamborn, K. R., Link, M. P., Kun, L., Billett, A. L., Marcus, K. C., Hurwitz, C. A., Young, J. A., Tarbell, N. J., Weinstein, H. J. 2002; 20 (14): 3081-3087

  Abstract

  To evaluate outcome and assess toxicity of children and adolescents with early-stage, favorable Hodgkin's disease treated with vinblastine, doxorubicin, methotrexate, and prednisone (VAMP) and low-dose, involved-field radiation.One hundred ten patients with clinical stages I and II, favorable (nonbulky) Hodgkin's disease were treated with four cycles of VAMP chemotherapy and 15 Gy involved-field radiation for those who achieved a complete response, or 25.5 Gy for those who achieved a partial response to two cycles of VAMP.With a median follow-up of 5.6 years (range, 1.1 to 10.4 years), the 5-year survival and event-free survival were 99% (lower confidence limit [CL], 97.4%) and 93% (lower CL, 88.6%), respectively. Factors associated with event-free survival of 100% were complete response to two cycles of VAMP and histology other than nodular sclerosing Hodgkin's disease (NSHD). No serious early or late toxicity has been observed. Patients presenting with clinical stages I and IIA, nonbulky disease involving fewer than three nodal sites have a projected survival and event-free survival of 100% and 97% (lower CL, 93%), respectively, at 5 years.Risk-adapted, combined-modality therapy using only four cycles of VAMP chemotherapy with 15 to 25.5 Gy of involved-field radiation for patients with early-stage/favorable Hodgkin's disease is highly effective and without demonstrable late effects. These results indicate that pediatric patients with stages I and II favorable Hodgkin's disease can be cured with limited therapy that does not include an alkylating agent, bleomycin, etoposide, or high-dose, extended-field radiation therapy.

  View details for DOI 10.1200/JCO.2002.12.101

  View details for Web of Science ID 000176920000007

  View details for PubMedID 12118021

• Bone marrow stroma-supported culture of T-lineage acute lymphoblastic leukemic cells predicts treatment outcome in children: a Pediatric Oncology Group study LEUKEMIA Winter, S. S., Sweatman, J., Shuster, J. J., Link, M. P., Amylon, M. D., Pullen, J., Camitta, B. M., Larson, R. S. 2002; 16 (6): 1121-1126

  Abstract

  Significant predictors of treatment outcome are poorly defined for patients with T-lineage acute lymphoblastic leukemia (T-ALL). A high WBC at diagnosis, which has traditionally been a predictor of poor response in T-ALL, has considerably weakened prognostic significance in the face of modern, more intensive chemotherapy. To test the hypothesis that bone marrow stroma-supported leukemic cell recovery might identify children at high risk for relapse, we measured the ex vivo recovery of T-ALL lymphoblasts from 29 newly diagnosed patients using a stromal cell co-culture assay. In all cases the T-ALL lymphoblasts showed an increase in recovery of T-ALL cells (RTC), ranging from 4 to 343%, in comparison to samples maintained without stroma. Since we were blinded to patient outcome in this case-control study, we then correlated patient outcome with RTC. The RTC for 18 patients in complete continuous remission (CCR) for greater than 4 years was stochastically larger than for the 11 patients who eventually relapsed (P = 0.011, by the two-sided Wilcoxon test). Furthermore, 100% of patients with an RTC of more than 26% had a CCR greater than 4 years while 78% of the patients with an RTC of less than 25% relapsed within 4 years. This is the first report to show that higher lymphoblast recovery may predict a more favorable outcome for children with T-ALL. A prospective study is needed to test whether stroma-supported leukemic cell recovery might serve as a basis for assigning risk-adjusted therapy.

  View details for DOI 10.1038/sj/leu/2402469

  View details for Web of Science ID 000176069600014

  View details for PubMedID 12040442

• Dose escalation and pharmacokinetics of pegylated liposomal doxorubicin (Doxil) in children with solid tumors: A pediatric oncology group study CLINICAL CANCER RESEARCH Marina, N. M., Cochrane, D., Harney, E., Zomorodi, K., Blaney, S., Winick, N., Bernstein, M., Link, M. P. 2002; 8 (2): 413-418

  Abstract

  To determine the maximum tolerated dose and pharmacokinetics of Doxil in children with recurrent or refractory solid tumors. Doxil is pegylated doxorubicin.Eligible patients were children with refractory tumors who had received cumulative anthracycline doses <300 mg/m(2). Cohorts of at least three patients each received escalating doses of Doxil starting at 40 mg/m(2) at 4-week intervals. If no dose-limiting toxicity occurred, dosages were escalated by increments of 10 mg/m(2) in subsequent cohorts. Originally, Doxil was administered over 60 min, but significant infusion reactions prompted longer infusion times of 4 h. Patients also received premedication with dexamethasone, ranitidine, and diphenhydramine 24 h before infusion, with ranitidine continued 24 h after infusion. Periodic blood samples were collected and plasma doxorubicin concentrations were quantified to characterize the pharmacokinetics of Doxil.Between January 1997 and June 2000, 22 children ages 4-21 years with refractory tumors were treated with Doxil. Most patients had received one to five prior chemotherapy regimens, and all but five had prior radiotherapy (two had no prior therapy). Doxil was escalated to a dosage of 70 mg/m(2). At that level, dose-limiting mucositis was seen during the first cycle in two of six patients, thus defining dose-limiting toxicity, and in one additional patient during a subsequent cycle. Grade 4 neutropenia lasting less than 7 days was documented in two of six patients. The dose-limiting toxicity among two of six patients at 70 mg/m(2) was grade 3 mucositis during the first cycle of therapy. Painful desquamating dermatitis of the hands and feet, palmar-plantar erythrodysesthesia, occurred in six patients. In two of those patients, palmar-plantar erythrodysesthesia started as grade 1 and progressed to grade 2 during subsequent courses. Mean estimates of central volume of distribution, clearance, and elimination half-life were 1.45 liters/m(2), 0.03 liter/h/m(2), and 36.4 h, respectively.The maximum tolerated dose of Doxil administered every 4 weeks to pediatric patients was 60 mg/m(2). The effect of Doxil on pediatric patients with malignancies remains to be determined and should be studied in pediatric Phase II trials.

  View details for Web of Science ID 000173908600013

  View details for PubMedID 11839657

• Phase II/III trial of etoposide and high-dose ifosfamide in newly diagnosed metastatic osteosarcoma: A Pediatric Oncology Group trial JOURNAL OF CLINICAL ONCOLOGY Goorin, A. M., Harris, M. B., Bernstein, M., Ferguson, W., Devidas, M., Siegal, G. P., Gebhardt, M. C., Schwartz, C. L., Link, M., Grier, H. E. 2002; 20 (2): 426-433

  Abstract

  The objectives of this trial were to estimate the response rate, progression-free survival, and overall survival of patients who received therapy with etoposide and high-dose ifosfamide, and to define the toxicity of this combination when provided with standard chemotherapy in patients with newly diagnosed metastatic osteosarcoma.Eligible patients received infusions of 100 mg/m(2) per day of etoposide and 3.5 g/m(2) per day of ifosfamide for 5 days. Therapy with granulocyte colony-stimulating factor was begun on day 6. This was repeated 3 weeks after therapy was begun. Response was determined at week 6 by both standard World Health Organization response criteria and by pathologic determination of tumor necrosis of the primary tumor.Forty-three patients were registered; 39 were assessable for response and 41 for toxicity and survival. Twenty-eight (68%) of 41 had metastatic sites only in the lung; 12 (29%) had metastatic sites in other bones with or without lung involvement. Four patients (10%) experienced complete response, and 19 patients (49%) experienced partial response, for an overall response rate of 59% +/- 8%. The projected 2-year progression-free survival (PFS) for the 28 patients with metastases to lungs was 39% +/- 11%. The projected 2-year PFS for the 12 patients with metastases to other bones (with or without pulmonary metastases) was 58% +/- 17%. Two patients died as a result of therapy toxicity. Eighty-three percent of patients had grade 4 neutropenia, and 29% had grade 4 thrombocytopenia. Ten patients (24%) had sepsis. Fanconi's syndrome was observed in five patients.The combination of etoposide and high-dose ifosfamide is effective induction chemotherapy for patients with metastatic osteosarcoma, despite significant associated myelosuppression sometimes complicated by infection and renal toxicity.

  View details for Web of Science ID 000173404000011

  View details for PubMedID 11786570

• Efficacy of ifosfamide and doxorubicin given as a phase II "window" in children with newly diagnosed metastatic rhabdomyosarcoma: A report from the Intergroup Rhabdomyosarcoma Study Group MEDICAL AND PEDIATRIC ONCOLOGY Sandler, E., Lyden, E., Ruymann, F., Maurer, H., Wharam, M., Parham, D., Link, M., Crist, W. 2001; 37 (5): 442-448

  Abstract

  The cure rate for children/adolescents with localized rhabdomyosarcoma (RMS) has tripled over the past 25 years, but patients with metastatic disease at presentation have not benefited similarly, and urgently need new therapy. We evaluated a new drug pair, ifosfamide + doxorubicin, for such patients.We estimated the complete and partial response rates (i.e., CR and PR) of 152 previously untreated children/adolescents with metastatic RMS entered on the IRS-IV pilot from July 1988 to October 1991 who received an "up-front window" of ifosfamide (1.8 gm/m(2)/day for 5 days) and doxorubicin (30 mg/m(2)/day for 2 days) given every 3 weeks for 12 weeks. This was followed by combination chemotherapy with vincristine, actinomycin D, and cyclophosphamide (VAC), given every 3 weeks for an additional 36 weeks.Of 115 patients evaluable for early response at 12 weeks, 28 (20%) had CR and 66 (43%) had PR. The ultimate CR rate was 52%. Overall, about one-third of patients survived. Prognostic factor analysis revealed that patients < 10 years old (P < 0.001), those with embryonal tumors (P = 0.002), or a GU primary site (P = 0.010), and those who lacked nodal disease (P = 0.041), and those who lacked bone or bone marrow metastasis (P < 0.001) fared better than did others.The 63% CR + PR rate achieved at 12 weeks and overall 5-year FFS seen with this drug pair is similar to that achieved with previously evaluated drug combinations. We conclude that ifosfamide/doxorubicin is highly active in advanced RMS, and should be considered for inclusion in frontline therapy for children with intermediate or high-risk RMS.

  View details for Web of Science ID 000171981700004

  View details for PubMedID 11745872

• Which patients with microscopic disease and rhabdomyosarcoma experience relapse after therapy? A report from the soft tissue sarcoma committee of the children's oncology group JOURNAL OF CLINICAL ONCOLOGY Smith, L. M., Anderson, J. R., Qualman, S. J., Crist, W. M., Paidas, C. N., Teot, L. A., Pappo, A. S., Link, M. P., Grier, H. E., Wiener, E. S., Breneman, J. C., Raney, R. B., Maurer, H. M., Donaldson, S. S. 2001; 19 (20): 4058-4064

  Abstract

  To identify which patients with rhabdomyosarcoma and microscopic residual disease (group II) are likely to not respond to therapy.Six hundred ninety-five patients with group II tumors received chemotherapy and 90% received radiation therapy on Intergroup Rhabdomyosarcoma Study (IRS)-I to IRS-IV (1972 to 1997). Tumors were subgrouped depending on the presence of microscopic residual disease only (subgroup IIa), resected positive regional lymph nodes, (subgroup IIb), or microscopic residual disease and resected positive regional lymph nodes (subgroup IIc).Overall, the 5-year failure-free survival rate (FFSR) was 73%, and patients with embryonal rhabdomyosarcoma treated on IRS-IV fared especially well (5-year FFSR, 93%; n = 90). Five-year FFSRs differed significantly by subgroup (IIa, 75% and n = 506; IIb, 74% and n = 101; IIc, 58% and n = 88; P = .0037) and treatment (IRS-I, 68%; IRS-II, 67%; IRS-III, 75%; IRS-IV, 87%; P < .001). Multivariate analysis revealed positive associations between primary site (favorable), histology (embryonal), subgroup IIa or IIb, treatment (IRS-III/IV), and better FFSRs. Patterns of treatment failure revealed local failure to be 8%, regional failure, 4%, and distant failure, 14%. The relapse pattern noted over the course of IRS-I to IRS-IV shows a decrease in the systemic relapse rates, particularly for patients with embryonal histology, suggesting that improvement in FFSRs is primarily a result of improved chemotherapy.Group II rhabdomyosarcoma has an excellent prognosis with contemporary therapy as used in IRS-III/IV, and those less likely to respond can be identified using prognostic factors: histology, subgroup, and primary site. Patients with embryonal rhabdomyosarcoma are generally cured, although patients with alveolar rhabdomyosarcoma or undifferentiated sarcoma, particularly subgroup IIc at unfavorable sites, continue to need better therapy.

  View details for Web of Science ID 000171634200009

  View details for PubMedID 11600608

• Controversies in the management of paratesticular rhabdomyosarcoma: is staging retroperitoneal lymph node dissection necessary for adolescents with resected paratesticular rhabdomyosarcoma? Seminars in pediatric surgery Wiener, E. S., Anderson, J. R., Ojimba, J. I., Lobe, T. E., Paidas, C., Andrassy, R. J., Raney, R. B., Qualman, S. J., Donaldson, S. S., Maurer, H. M., Link, M. P., Crist, W. M., Grier, H. E. 2001; 10 (3): 146-152

  Abstract

  Use of retroperitoneal lymph node dissection (RPLND) in paratesticular rhabdomyosarcoma (PTRMS) is controversial and has changed over the past 2 decades. The Intergroup Rhabdomyosarcoma Study Group (IRSG) required ipsilateral RPLND (IRPLND) for all patients with PTRMS treated on IRS-III (1984-91), but changed to clinical evaluation of RPLNs using computerized tomography (CT) in IRS-IV (1991 through 1997). In IRS-IV, only those patients with identified lymph node involvement on CT required surgical evaluation of the RPLNs. Nodal radiation therapy was administered only to patients with RPLNs recognized as positive; such patients received more intensive chemotherapy as well. Thus, they compared the incidence of recognized RPLN involvement using these 2 different approaches. They then analyzed patient outcome to determine whether this change in management affected outcome.Eligible patients with group I or II PTRMS who were treated on IRS III (n = 100) or IRS IV (n = 134) were analyzed. Failure-free survival (FFS) and survival (S) rates were estimated using the Kaplan-Meier method and compared using the log-rank test.There was a significant change in the distribution of patients with group I versus II tumors from IRS-III to IRS-IV (group I, 68% in IRS-III versus 82% in IRS-IV). This was the result of decreased node recognition when CT was used to stage RPLNs in IRS-IV and was most notable for adolescents (>10 years of age). Overall, 3-year FFS was 92% for patients treated on IRS-III and 86% for those treated on IRS-IV (P =.10), whereas survival estimates were 96% and 92%, respectively (P =.30). Adolescents were at higher risk of RPLN relapse than were children (<10 years of age) and their FFS and survival were worse, regardless of IRS protocol. Furthermore, adolescents with recognized group II tumors experienced better 3-year FFS than those with group I tumors on IRS-IV (100% versus 68%, P =.06), most likely as a result of receiving radiotherapy and intensified chemotherapy.Use of only CT scan evaluation of RPLN in IRS-IV led to a decrease in identification of RPLN involvement in boys who present with localized PTRMS, and a higher rate of regional relapse as compared with IRS-III. Adolescents had much higher likelihood of RPLN disease, and they fared significantly worse than did younger children on both studies. Furthermore, adolescent boys with group I tumors experienced worse FFS than those with Group II tumors on IRS-IV, probably because some patients with group II tumors were not identified by CT imaging and thus received less effective therapy. These data suggest that adolescents should have ipsilateral RPLN dissection as part of their routine staging, and those with positive lymph nodes require intensified chemotherapy as well as nodal irradiation.

  View details for PubMedID 11481652

• Presurgical window of carboplatin and surgery and multidrug chemotherapy for the treatment of newly diagnosed metastatic or unresectable osteosarcoma: Pediatric Oncology Group trial JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY Ferguson, W. S., Harris, M. B., Goorin, A. M., Gebhardt, M. C., Link, M. P., Shochat, S. J., Siegal, G. P., Devidas, M., Grier, H. E. 2001; 23 (6): 340-348

  Abstract

  Relapse remains a significant problem in patients with metastatic osteosarcoma. The response to carboplatin of patients with newly diagnosed metastatic or unresectable osteosarcoma was assessed in an upfront phase II window, which was followed-up by surgery and intensive multiagent chemotherapy.Thirty-seven patients, ages 3 to 23 years with histologically confirmed diagnoses of osteosarcoma, were treated between January 1992 and November 1994 with carboplatin 1,000 mg/m2 per dose administered as a 48-hour continuous infusion. Two courses were administered in 3-week intervals, depending on marrow recovery. After radiographic reevaluation, patients underwent surgical removal of tumor (if feasible) and then 40 weeks of chemotherapy with high-dose methotrexate, ifosfamide, doxorubicin, and cisplatin.One of the 37 evaluable patients demonstrated a partial response to carboplatin; there were no complete responses. Patients were additionally analyzed by the response of pulmonary metastases to therapy and the extent of tumor necrosis of the primary lesion. By these criteria, 8 of 37 (22%) of patients showed a response at one or more sites, whereas 20 of 37 (54%) had unequivocal disease progression. Severe myelosuppression was the major toxicity. The projected 3-year event-free and overall survival rates were 23.9% and 31.9%, respectively. Only 1 of 17 patients with unresectable disease or distant bone metastases remains alive, in contrast to 6 of 17 patients with the lung as their only metastatic site and two of three patients with resected regional bone metastases.Continuous-infusion carboplatin demonstrated limited activity as an upfront agent in patients with metastatic osteosarcoma at diagnosis, even at doses that result in severe and prolonged myelosuppression. Patients with isolated pulmonary metastases or resectable bone metastases have a longer median survival time and greater chance of long-term survival than do patients with unresectable bone disease, for whom the prognosis remains dismal.

  View details for Web of Science ID 000170884300005

  View details for PubMedID 11563767

• What constitutes optimal therapy for patients with rhabdomyosarcoma of the female genital tract? Annual Meeting of the American-Society-of-Pediatric-Hematology/Oncology Arndt, C. A., Donaldson, S. S., Anderson, J. R., Andrassy, R. J., Laurie, F., Link, M. P., Raney, R. B., Maurer, H. M., Crist, W. M. JOHN WILEY & SONS INC. 2001: 2454–68

  Abstract

  Factors affecting outcome for rhabdomyosarcoma (RMS) of the female genital tract in patients treated on Intergroup Rhabdomyosarcoma Study Group (IRSG) protocols I-IV were evaluated to define optimal therapy.Records of 151 patients with tumors of the female genital tract who were treated on IRSG protocols I-IV were reviewed for details regarding chemotherapy, surgery, radiotherapy (RT), and outcome.The overall 5-year survival was 82%, (87% for patients with locoregional tumors). Chemotherapy was primarily vincristine, actinomycin-D, and cyclophosphamide (VAC) based. Local therapy was surgery alone in 42% of patients, surgery plus RT in 19% of patients, biopsy plus RT in 12% of patients, and biopsy without RT in 21% of patients. The rate of hysterectomy decreased from 48% in IRS-I/II to 22% in IRS-III/IV with an increase in the use of RT from 23% in IRS-II to 45% in IRS-IV and continued excellent survival. Many patients with vaginal primary tumors received delayed RT or had it omitted on later studies with excellent outcome. For patients with localized embryonal/botryoid tumors, there were no significant differences in 5-year survival among patients with tumors at different sites or among patients treated on IRS-I-IV. In patients with Group I-III tumors, 43% of deaths were from toxicity. Analysis of prognostic factors, with toxic deaths censored, revealed that an age of 1-9 years at the time of diagnosis, noninvasive tumors, and the use of IRS-II or IRS-IV treatments were associated significantly with better outcome. Patients ages 1-9 years fared best (5-year survival of 98%) and patients outside of this age range especially benefited from the intensified therapy used in IRS-III or IRS-IV (5-year survival of 67% on the IRS-I/II vs. 90% in IRS-III/IV).Localized female genital RMS usually is curable with combination chemotherapy, a conservative surgical approach, and the use of RT for selected patients.

  View details for Web of Science ID 000169348200032

  View details for PubMedID 11413538

• Thyroid carcinoma after successful treatment of osteosarcoma: A report of three patients JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY Verneris, M., McDougall, I. R., Becton, D., Link, M. P. 2001; 23 (5): 312-315

  Abstract

  We report three cases of papillary thyroid carcinoma occurring after successful treatment of osteosarcoma. Only one of the three patients received radiation therapy (to the chest) as part of the primary treatment of osteosarcoma. The onset of thyroid carcinoma occurred between 8 and 16 years from the cessation of osteosarcoma therapy. All patients are alive and disease-free from both malignancies. Whereas the association between osteosarcoma and thyroid carcinoma has not previously been recognized, there have been five case reports of these two entities occurring in the same patient. Three of these cases occurred in patients with Werner syndrome. None of the patients reported here had physical stigmata of Werner syndrome or a family history consistent with a hereditary cancer syndrome. Thyroid carcinoma occurs infrequently in patients with osteosarcoma, but in view of the rarity of these two disorders, this association may represent an inherited predisposition to these malignancies.

  View details for Web of Science ID 000169804200014

  View details for PubMedID 11464990

• Attitudes and practices among pediatric oncologists regarding end-of-life care: Results of the 1998 American Society of Clinical Oncology survey JOURNAL OF CLINICAL ONCOLOGY Hilden, J. M., Emanuel, E. J., Fairclough, D. L., Link, M. P., Foley, K. M., Clarridge, B. C., Schnipper, L. E., Mayer, R. J. 2001; 19 (1): 205-212

  Abstract

  In 1998, the American Society of Clinical Oncology (ASCO) surveyed its membership to assess the attitudes, practices, and challenges associated with end-of-life care of patients with cancer. In this report, we summarize the responses of pediatric oncologists and the implications for care of children dying from cancer.The survey consisted of 118 questions, covering eight categories. All ASCO members in the United States, Canada, and the United Kingdom were mailed a survey, which was completed by 228 pediatric oncologists. Predictors of particular attitudes and practices were identified using stepwise logistic regression analysis. Potential predictors were age, sex, religious affiliation, importance of religious beliefs, recent death of a relative, specialty, type of practice (rural or urban, academic or nonacademic), amount of time spent in patient care, number of new patients in the past 6 months, and number of patients who died in the past year.Pediatric oncologists reported a lack of formal courses in pediatric palliative care, a strikingly high reliance on trial and error in learning to care for dying children, and a need for strong role models in this area. The lack of an accessible palliative care team or pain service was often identified as a barrier to good care. Communication difficulties exist between parents and oncologists, especially regarding the shift to end-of-life care and adequate pain control.Pediatric oncologists are working to integrate symptom control, psychosocial support, and palliative care into the routine care of the seriously ill child, although barriers exist that make such comprehensive care a challenge.

  View details for Web of Science ID 000166228500026

  View details for PubMedID 11134214

• New recurring cytogenetic abnormalities and association of blast cell karyotypes with prognosis in childhood T-cell acute lymphoblastic leukemia: a Pediatric Oncology Group report of 343 cases BLOOD Schneider, N. R., Carroll, A. J., Shuster, J. J., Pullen, D. J., Link, M. P., Borowitz, M. J., Camitta, B. M., Katz, J. A., Amylon, M. D. 2000; 96 (7): 2543-2549

  Abstract

  To further define the cytogenetic differences between B-cell lineage (B-lineage) acute lymphoblastic leukemia (ALL) and T-cell lineage ALL (T-ALL) and to determine the prognostic value of cytogenetics in childhood T-ALL, the blast cell karyotypes of 343 cases of pediatric T-ALL, the largest series reported to date, were evaluated. Cytogenetics were performed in a single central laboratory, and the children were treated using a single Pediatric Oncology Group protocol. Clear differences between the karyotypic characteristics of B-lineage ALL and T-ALL were confirmed. This study suggests that there may be survival differences associated with some T-ALL blast cell karyotypes. Better survival is associated with only normal karyotypes and with t(10;14) (translocation of chromosomes 10 and 14); worse survival is associated with the presence of any derivative chromosome. Two new recurring chromosome aberrations previously not reported in T-ALL were found: del(1)(p22) and t(8;12)(q13;p13). Ten aberrations found in this series, which were reported only once previously in T-ALL, can now be considered recurring abnormalities in T-ALL. All 12 of these new recurring aberrations are targets for discovery and characterization of new genes that are important in T-cell development and leukemogenesis.

  View details for Web of Science ID 000089552500033

  View details for PubMedID 11001909

• Benefit of intensified therapy for patients with local or regional embryonal rhabdomyosarcoma: Results from the Intergroup Rhabdomyosarcoma Study IV JOURNAL OF CLINICAL ONCOLOGY Baker, K. S., Anderson, J. R., Link, M. P., Grier, H. E., Qualman, S. J., Maurer, H. M., Breneman, J. C., Wiener, E. S., Crist, W. M. 2000; 18 (12): 2427-2434

  Abstract

  To compare failure-free survival (FFS) and survival for patients with local or regional embryonal rhabdomyosarcoma treated on the Intergroup Rhabdomyosarcoma Study (IRS)-IV with that of comparable patients treated on IRS-III.Patients were retrospectively classified as low- or intermediate-risk. Low-risk patients were defined as those with primary tumors at favorable sites, completely resected or microscopic residual, or orbit/eyelid primaries with gross residual disease and tumors less than 5 cm at unfavorable sites but completely resected. Intermediate-risk patients were all other patients with local or regional tumors.Three-year FFS improved from 72% on IRS-III to 78% on IRS-IV for patients with intermediate-risk embryonal rhabdomyosarcoma (P =.02). Subset analysis revealed two groups that benefited most from IRS-IV therapy. FFS at 3 years for patients with resectable node-positive or unresectable (group III) embryonal rhabdomyosarcoma arising at certain favorable sites (head and neck [not orbit/eyelid or parameningeal] and genitourinary [not bladder or prostate]) improved from 72% on IRS-III to 92% on IRS-IV (P =.01). Similarly, 3-year FFS for patients with completely resected tumor or with only microscopic disease remaining (group I or II) at unfavorable sites improved from 71% on IRS-III to 86% on IRS-IV (P =.04). Only patients with unresectable embryonal rhabdomyosarcoma (group III) at unfavorable sites had no improvement in outcome on IRS-IV (3-year FFS for IRS-III and IRS-IV, 72% and 75%, respectively; P =.31).IRS-IV therapy benefited certain subgroups of patients with intermediate-risk embryonal rhabdomyosarcoma. A doubling of the intensity of cyclophosphamide (or ifosfamide equivalent) dosing per cycle between IRS-III and IRS-IV is thought to be a key contributing factor for this improvement.

  View details for Web of Science ID 000087708300011

  View details for PubMedID 10856103

• Effects of cranial radiation in children with high risk T cell acute lymphoblastic leukemia: a Pediatric Oncology Group report LEUKEMIA Laver, J. H., Barredo, J. C., Amylon, M., Schwenn, M., Kurtzberg, J., Camitta, B. M., Pullen, J., Link, M. P., Borowitz, M., Ravindranath, Y., Murphy, S. B., Shuster, J. 2000; 14 (3): 369-373

  Abstract

  Contemporary chemotherapy has significantly improved event-free survival among patients with T cell-lineage acute lymphoblastic leukemia (T-ALL). Unlike B-precursor ALL, most investigators are still using cranial radiation (CRT) and are hesitant to rely solely on intrathecal therapy for T-ALL. In this study we assessed the effects of CRT upon event-free survival and central nervous system (CNS) relapses in a cohort of children with high risk features of T cell leukemia. In a series of six consecutive studies (1987-1995) patients were non-randomly assigned their CNS prophylaxis per individual protocol. These protocols were based on POG 8704 which relied on rotating drug combinations (cytarabine/cyclophosphamide, teniposide/Ara-C, and vincristine/doxorubicin/6-MP/prednisone) postinduction. Modifications such as high-dose cytarabine, intermediate-dose methotrexate, and the addition of G-CSF, were designed to give higher CNS drug levels (decreasing the need for CRT), to eliminate epidophyllotoxin (decreasing the risk of secondary leukemia), and to reduce therapy-related neutropenia (pilot studies POG 9086, 9295, 9296, 9297, 9398). All patients included in this analysis qualified for POG high risk criteria, WBC >50000/mm3 and/or CNS leukemia. Patients without CNS involvement received 16 doses of age-adjusted triple intra-thecal therapy (TIT = hydrocortisone, MTX, and cytarabine) whereas patients with CNS disease received three more doses of TIT during induction and consolidation. Patients who received CRT were treated with 2400 cGy (POG 8704) or 1800 cGy (POG 9086 and 9295). CNS therapy included CRT in 144 patients while the remaining 78 patients received no radiation by original protocol design. There were 155 males and 57 females with a median age of 8.2 years. The median WBC for the CRT+ and CRT- patients were 186000/mm3 and 200000/mm3, respectively. CNS involvement at diagnosis was seen in 16% of the CRT+ and 23% of the CRT- groups. The complete continuous remission rate (CCR) was not significantly different for the irradiated vs. non-irradiated groups (P = 0.46). The 3-year event-free survival was 65% (s.e. 6%) and 63% (s.e. 4%) for the non-irradiated vs. the radiated group. However, the 3-year CNS relapse rate was significantly higher amongst patients who did not receive CRT; 18% (s.e. 5%) vs. 7% (s.e. 3%) in the irradiated group (P = 0.012). Our analysis in a non-randomized setting, suggests that CRT did not significantly correlate with event-free survival but omitting it had an adverse effect on the CNS involvement at the time of relapse.

  View details for Web of Science ID 000085748400004

  View details for PubMedID 10720128

• Burkitt lymphoma is immunophenotypically different from Burkitt-like lymphoma in young persons International Conference on Malignant Lymphoma Hutchison, R. E., Finch, C., Kepner, J., Fuller, C., Bowman, P., Link, M., Schwenn, M., Laver, J., Desai, S., Barrett, D., Murphy, S. B. OXFORD UNIV PRESS. 2000: 35–38

  Abstract

  Burkitt-like lymphoma (BLL) is a provisional category of B-cell lymphoma which is morphologically intermediate between Burkitt lymphoma (BL) and large B-cell lymphoma (LBCL). The clinical significance of this morphology is controversial.We examined 41 cases of pediatric B-cell lymphoma by immunohistochemistry for proteins associated with proto-oncogenes c-myc, BCL-2 and BCL-6 and a subset of cases (with adequate slides) for a proliferation-associated marker (Ki-67) and for apoptosis (Apop-Tag). Sixteen cases of BLL, thirteen cases of BL and twelve cases of LBCL were examined.Our results showed BCL-6 expression in 16 of 16 BLL, 4 of 13 BL, and 9 of 12 LBCL; c-myc expression in 14 of 15 BLL, 9 of 13 BL, and 12 of 12 LBCL; and BCL-2 expression in 2 of 16 BLL, 9 of 13 BL, and 6 of 12 LBCL. Mean apoptotic index for BLL was 10.3% (n = 6); for BL was 17.1% (n = 5); and for LBCL was 10.9% (n = 6). Ki-67 was diffusely reactive in all cases tested. There was a significantly higher proportion of BLL than BL which expressed BCL-6 (P = 0.0001).Labeling for BCL-6 distinguishes BLL from BL. It is likely that in children in North America, BLL is biologically distinct from BL and more closely resembles a subset of LBCL.

  View details for Web of Science ID 000085882800007

  View details for PubMedID 10707776

• 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 LEUKEMIA Pullen, J., Shuster, J. J., Link, M., Borowitz, M., Amylon, M., Carroll, A. J., Land, V., Look, A. T., McIntyre, B., Camitta, B. 1999; 13 (11): 1696-1707

  Abstract

  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.

  View details for Web of Science ID 000083664000005

  View details for PubMedID 10557041

• Intensive high-dose asparaginase consolidation improves survival for pediatric patients with T cell acute lymphoblastic leukemia and advanced stage lymphoblastic lymphoma: a Pediatric Oncology Group study LEUKEMIA Amylon, M. D., Shuster, J., Pullen, J., Berard, C., Link, M. P., Wharam, M., Katz, J., Yu, A., Laver, J., Ravindranath, Y., Kurtzberg, J., Desai, S., Camitta, B., Murphy, S. B. 1999; 13 (3): 335-342

  Abstract

  This study was designed to test the hypothesis that high-dose asparaginase consolidation therapy improves survival in pediatric patients with T cell acute lymphoblastic leukemia and advanced stage lymphoblastic lymphoma. Five hundred and fifty-two patients (357 patients with T cell acute lymphoblastic leukemia (ALL) and 195 patients with advanced stage lymphoblastic lymphoma) were enrolled in POG study 8704 (T-3). Treatment included rotating combinations of high-dose myelosuppressive chemotherapy agents proven to be effective in T cell ALL in other POG group-wide or local institutional protocols (including vincristine, doxorubicin, cyclophosphamide, prednisone, asparaginase, teniposide, cytarabine and mercaptopurine). After achieving a complete remission (CR), patients were randomized to receive or not receive high-dose intensive asparaginase consolidation (25,000 IU/m2) given weekly for 20 weeks by intramuscular injection. Intrathecal chemotherapy (methotrexate, hydrocortisone and cytarabine) was given to prevent CNS disease, and CNS irradiation was used only for patients with leukemia and an initial WBC of >50,000/microl or patients with active CNS disease at diagnosis. CR was achieved in 96% of patients. The high-dose asparaginase regimen was significantly superior to the control regimen for both the leukemia and lymphoma subgroups. Four-year continuous complete remission rate (CCR) for the leukemia patients was 68% (s.e. 4%) with asparaginase as compared to 55% (s.e. 4%) without. For the lymphoma patients, 4-year CCR was 78% (s.e. 5%) with asparaginase and 64% (s.e. 6%) in the controls. The overall one-sided logrank test had a P value <0.001 favoring asparaginase, while corresponding values were P = 0.002 for ALL and P = 0.048 lymphoblastic lymphoma. Toxicities were tolerable, but there were 18 failures due to secondary malignancies (16 with non-lymphocytic leukemia or myelodysplasia). Neither WBC at diagnosis (leukemia patients) nor lymphoma stage were major prognostic factors. We conclude that when added to a backbone of effective rotating agents, repeated doses of asparaginase during early treatment improve the outcome for patients with T cell leukemia and advanced stage lymphoblastic lymphoma.

  View details for Web of Science ID 000079086000004

  View details for PubMedID 10086723

• Treatment of localized primary non-Hodgkin's lymphoma of bone in children: A Pediatric Oncology Group study JOURNAL OF CLINICAL ONCOLOGY Suryanarayan, K., Shuster, J. J., Donaldson, S. S., Hutchison, R. E., Murphy, S. B., Link, M. P. 1999; 17 (2): 456-459

  Abstract

  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.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.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.Localized PLB is curable in most children and adolescents with a 9-week chemotherapy regimen of modest intensity, and radiotherapy is an unnecessary adjunct.

  View details for Web of Science ID 000078384500005

  View details for PubMedID 10080585

• Childhood acute lymphoblastic leukemia with the MLL-ENL fusion and t(11;19)(q23;p13.3) translocation JOURNAL OF CLINICAL ONCOLOGY Rubnitz, J. E., Camitta, B. M., Mahmoud, H., Raimondi, S. C., Carroll, A. J., Borowitz, M. J., Shuster, J. J., Link, M. P., Pullen, D. J., Downing, J. R., Behm, F. G., Pui, C. H. 1999; 17 (1): 191-196

  Abstract

  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.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.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.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.

  View details for Web of Science ID 000077927400024

  View details for PubMedID 10458233

• Acute lymphoblastic leukemia with the (8;14)(q24;q32) translocation and FAB L3 morphology associated with a E-precursor immunophenotype: the Pediatric Oncology Group experience LEUKEMIA Navid, F., Mosijczuk, A. D., Head, D. R., Borowitz, M. J., Carroll, A. J., Brandt, J. M., Link, M. P., Rozans, M. K., Thomas, G. A., Schwenn, M. R., Shields, D. J., Vietti, T. J., Pullen, D. J. 1999; 13 (1): 135-141

  Abstract

  Five pediatric patients are described with acute lymphoblastic leukemia (ALL) who at presentation had clinical findings suggestive of B cell ALL and lymphoblasts with FAB L3 morphology and the characteristic t(8;14)(q24;q32). However, the leukemia cells of all five patients failed to express surface immunoglobulin (sIg) and kappa or lambda light chains. Based on initial immunophenotyping results consistent with B-precursor ALL, four of these cases were initially treated with conventional ALL chemotherapy. These four patients were switched to B cell ALL treatment protocols once cytogenetic results became available revealing the 8;14 translocation. The fifth case was treated with B cell ALL therapy from the outset. Four of the five patients are in complete remission at 64, 36, 29 and 13 months from diagnosis. One patient relapsed and died 6 months after initial presentation. These five unusual cases with clinical B cell ALL, the t(8;14), and FAB L3 morphology, but negative sIg, demonstrate the importance of careful and multidisciplinary evaluation of leukemic cells with morphology, cytochemistry, immunophenotyping and cytogenetic analysis. Future identification of patients with this profile will allow us to expand our knowledge regarding prognostic significance and optimal treatment for this rare subgroup of patients.

  View details for Web of Science ID 000078262700022

  View details for PubMedID 10049049

• Treatment of metastatic osteosarcoma at diagnosis: A pediatric oncology group study JOURNAL OF CLINICAL ONCOLOGY Harris, M. B., Gieser, P., Goorin, A. M., Ayala, A., Shochat, S. J., Ferguson, W. S., Holbrook, T., Link, M. P. 1998; 16 (11): 3641-3648

  Abstract

  To estimate the duration of survival (S) of patients with metastatic osteosarcoma (MOS) at diagnosis treated with a multiagent, ifosfamide-containing chemotherapeutic and surgical regimen and to evaluate the toxicity of this regimen.Thirty patients aged younger than 30 years received two courses of ifosfamide followed by surgery on the primary tumor and metastatic sites. Patients then received a postsurgical multiagent chemotherapeutic regimen that consisted of high-dose methotrexate (HDMTX), ifosfamide, doxorubicin, and cisplatin.The 5-year event-free survival (EFS) rate was 46.7% (95% confidence interval [CI]; 28.5 to 64.9) and 5-year S rate was 53.3% (95% CI; 35.1 to 71.5). Three patients with bone metastases and one patient with lymph node metastases died. Twenty-six patients presented with pulmonary metastatic nodules only. Eight of these patients had at least eight nodules at diagnosis and had an estimated 5-year EFS rate of 25.0% compared with 66.7% for the 18 patients with less than eight nodules (P=.06). Fourteen patients presented with bilateral lung metastases and had a 5-year EFS rate of 35.7% compared with the 12 patients who presented with unilateral involvement and had a 5-year EFS rate of 75.0% (P=.03). The hematopoietic toxicity experienced by the patients during the entire regimen was relatively mild. Seven patients had renal toxicity characterized by hypophosphatemia and/or hypokalemia.This ifosfamide-containing regimen is tolerable and effective in the treatment of patients with osteosarcoma (OS) who present with lung metastases. However, better regimens are required for this group of patients.

  View details for Web of Science ID 000076742000024

  View details for PubMedID 9817286

• A multidisciplinary study investigating radiotherapy in Ewing's sarcoma: End results of POG #8346 39th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology Donaldson, S. S., Torrey, M., Link, M. P., GLICKSMAN, A., Gilula, L., Laurie, F., Manning, J., Neff, J., Reinus, W., Thompson, E., Shuster, J. J. ELSEVIER SCIENCE INC. 1998: 125–35

  Abstract

  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.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.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%.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.

  View details for Web of Science ID 000075901400017

  View details for PubMedID 9747829

• Cancer care during the last phase of life JOURNAL OF CLINICAL ONCOLOGY Schnipper, L., Bitran, J. D., Blank, L. L., Blum, D., BROCK, D., Bruera, E., Emanuel, E. J., Foley, K. M., Gordon, D. S., Hilden, J. M., Kagan, R. A., Levy, M. H., Lichter, A. S., Link, M. P., Penley, W. C., Smith, T. J., STANLEY, K., Stovall, E., Tokaz, L. K., Wood, W. C., MAYER, R. 1998; 16 (5): 1986-1996

  Abstract

  EXECUTIVE SUMMARY: The American Society of Clinical Oncology (ASCO) believes that it is the oncologists' responsibility to care for their patients in a continuum that extends from the moment of diagnosis throughout the course of the illness. In addition to appropriate anticancer treatment, this includes symptom control and psychosocial support during all phases of care, including those during the last phase of life. In an effort to assure that all patients and their families have access to optimal care at the end of life, ASCO firmly believes it is essential to emphasize a humane system of cancer care based on the following principles: Cancer care is centered around the longstanding and continuous relationship between the primary oncologist or other physician with training and interest in end-of-life care and the patient; Cancer care is responsive to the patient's wishes and to the parents' wishes if the patient is a child; Cancer care is based on truthful, sensitive, empathic communication with the patient, and in the case of pediatric patients, that care is both family centered as well as child focused; and Cancer care optimizes quality of life throughout the course of an illness through meticulous attention to the myriad physical, spiritual, and psychosocial needs of the patient and family. To reach these goals, ASCO has identified numerous obstacles that hinder delivery of high-quality end-of-life care and offers recommendations for improvements. ASCO is committed to informing its membership and the public about the significant barriers to optimal care at the end of life, and advocating legislative and regulatory changes that will eliminate these barriers.

  View details for Web of Science ID 000073415900048

  View details for PubMedID 9586919

• Randomized trial of r-metHu granulocyte colony-stimulating factor in an intensive treatment for T-cell leukemia and advanced-stage lymphoblastic lymphoma of childhood: A pediatric oncology group pilot study JOURNAL OF CLINICAL ONCOLOGY Laver, J., Amylon, M., Desai, S., Link, M., Schwenn, M., Mahmoud, H., Shuster, J. 1998; 16 (2): 522-526

  Abstract

  Contemporary chemotherapy has significantly improved the event-free survival (EFS) among patients with T-cell disease. However, myelosuppression has been a significant adverse effect of this approach. In this study, we assessed the impact of r-metHu granulocyte colony-stimulating factor (G-CSF) on the period of neutropenia, number of days of hospitalization, and delays in subsequent administration of chemotherapy in a cohort of patients with T-cell leukemia (T-ALL) or advanced stage lymphoblastic lymphoma (ASLL).This open-label, randomized trial incorporated r-metHuG-CSF into the induction and two consecutive continuation-therapy cycles of our intensive program for T-cell malignancies. In the induction phase, r-metHuG-CSF was given after two different combinations of chemotherapy, one of which included vincristine, prednisone, cyclophosphamide, and adriamycin and the other a continuous infusion of high-dose ara-C and L-asparaginase. In the two continuation-therapy cycles, r-metHuG-CSF was given following the combination of vincristine, adriamycin, prednisone, and 6-mercaptopurine (MP) and after continuous infusion of high-dose cytarabine (ara-C).Fifty-six patients with T-ALL and 33 with ASLL were enrolled onto study from April 1994 to December 1995. Our data show no significant difference in number of days of absolute neutrophil count (ANC) less than 500/microL, hospitalizations, or delays in therapy in the induction phase. However, in the continuation-therapy phase the number of days of ANC less than 500/microL was significantly shorter (P = .017) on the G-CSF-arm without significantly affecting the number of days of hospitalizations or delays in therapy.r-metHuG-CSF did not significantly affect the period of neutropenia, hospitalization, or delays in therapy in the induction phase, whereas in the two cycles of continuation therapy, it significantly shortened the period of neutropenia.

  View details for Web of Science ID 000071747900017

  View details for PubMedID 9469336

• 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 BLOOD Hunger, S. P., Fall, M. Z., Camitta, B. M., Carroll, A. J., Link, M. P., Lauer, S. J., Mahoney, D. H., Pullen, D. J., Shuster, J. J., Steuber, C. P., Cleary, M. L. 1998; 91 (3): 1021-1028

  Abstract

  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.

  View details for Web of Science ID 000071644000036

  View details for PubMedID 9446665

• Fractionated cyclophosphamide and back to back high dose methotrexate and cytosine arabinoside improves outcome in patients with stage III high grade small non-cleaved cell lymphomas (SNCCL): A randomized trial of the Pediatric Oncology Group MEDICAL AND PEDIATRIC ONCOLOGY Brecher, M. L., Schwenn, M. R., Coppes, M. J., Bowman, W. P., Link, M. P., Berard, C. W., Shuster, J. J., Murphy, S. B. 1997; 29 (6): 526-533

  Abstract

  The Pediatric Oncology Group (POG) conducted a two-arm, randomized study for the treatment of children and adolescents with stage III small, non-cleaved cell lymphoma (SNCCL). Regimen A, based on the group's previous best treatment for this group of patients, included cyclophosphamide (CTX) and high-dose methotrexate (MTX), as well as vincristine (VCR), prednisone (PRED), and intrathecal (IT) chemoprophylaxis. Regimen B, based on a single institution pilot study (Total B therapy), consisted of two rapidly alternating chemotherapy combinations (CTX, VCR, doxorubicin; MTX, and cytarabine (Ara-C) plus coordinated IT chemotherapy.One hundred thirty-four consecutive patients were entered on this study. Seventy patients were randomized to Regimen A, and 64 patients to Regimen B. One hundred and twenty-two patients are eligible for response.Complete remission (CR) was achieved by 81% (52/64) of patients on Regimen A, and 95% (55/58) of patients on Regimen B (p=0.014 one-sided). The two-year event-free survival (EFS) is 64% (SE=6%) on Regimen A, and 79% (SE=6%) on Regimen B (p=0.027 by one-sided logrank test). No patient has relapsed on either regimen after a year from diagnosis, although one patient had a second malignancy at day 371. Severe, but manageable, hematologic toxicity was seen in the majority of patients on both regimens, but was more frequent on Regimen B.We conclude that the cure rate in stage III SNCCL is significantly improved with the use of a short, six-month chemotherapy regimen of fractionated CTX alternated with coordinated MTX and Ara-C. Results suggest that drug schedule, not simple drug selection, influences outcome.

  View details for Web of Science ID A1997XY75800002

  View details for PubMedID 9324339

• Treatment of children and young adults with early-stage non-Hodgkin's lymphoma NEW ENGLAND JOURNAL OF MEDICINE Link, M. P., Shuster, J. J., Donaldson, S. S., Berard, C. W., Murphy, S. B. 1997; 337 (18): 1259-1266

  Abstract

  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.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.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.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.

  View details for Web of Science ID A1997YC92000002

  View details for PubMedID 9345074

• Lack of ETV6 (TEL) gene rearrangements or p16(INK4A)/p15(INK4B) homozygous gene deletions in infant acute lymphoblastic leukemia LEUKEMIA Maloney, K. W., Rubnitz, J. E., Cleary, M. L., Frankel, L. S., Hakami, N., Link, M. P., Pullen, D. J., Hunger, S. P. 1997; 11 (7): 979-983

  Abstract

  Acute lymphoblastic leukemia (ALL) occurring in infants less than 1 year of age differs clinically and biologically from that observed in older children. Cytogenetically, 11q23 translocations are detected in approximately 50% of infant ALLs and fuse the 11q23 gene HRX with a variety of partner chromosomal loci. Overall, HRX rearrangements are detected molecularly in 70-80% of infant ALLs as compared to 5-7% of ALLs arising in older children. Two recently described molecular abnormalities in childhood ALL are ETV6 gene rearrangements and homozygous deletions of p16(INK4A) and/or p15(INK4B). Each of these abnormalities occurs in 15-20% of all childhood ALLs, and neither can be accurately identified by routine cytogenetic analyses. The incidence of these genetic abnormalities and their potential relationship to HRX gene status in infant ALL is unknown. Using Southern blot analyses, we determined ETV6 and p16(INK4A)/p15(INK4B) gene status in a cohort of infant ALLs. No ETV6 rearrangements or homozygous deletions (n=69) or homozygous p16(INK4A) and/or p15(INK4B) gene deletions (n=54) were detected in any of the infant ALLs. Therefore, ETV6 and p16(INK4A)/p15(INK4B) do not play a significant role in the pathogenesis of infant ALL, further emphasizing the distinctive biology of this subset of leukemias.

  View details for Web of Science ID A1997XK27800010

  View details for PubMedID 9204978

• A feasibility, toxicity, and early response study of etoposide, ifosfamide, and vincristine for the treatment of children with rhabdomyosarcoma: A report from the intergroup rhabdomyosarcoma study (IRS) IV pilot study JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY Arndt, C., Tefft, M., Gehan, E., Anderson, J., Jenson, M., Link, M., Donaldson, S., Breneman, J., Wiener, E., Webber, B., Maurer, H. 1997; 19 (2): 124-129

  Abstract

  The purpose of this study was to determine the feasibility, toxicity, and early response of patients with clinical group III rhabdomyosarcoma (RMS) to a chemotherapy regimen of etoposide (ETOP), ifosfamide (IFOS), and vincristine (VCR) with hyperfractionated radiation therapy (XRT).Sixty-eight patients aged < 21 years, previously untreated, with clinical group III RMS or undifferentiated sarcoma with normal organ function were eligible for this study. Chemotherapy was as follows: weeks 0-8: IFOS 1.8 g/m2/day X 5 days every 3 weeks X 3 (with mesna), ETOP 100 mg/m2/day X 5 days every 3 weeks X 3, and VCR 1.5 mg/m2/week X 9; weeks 9-16: hyperfractionated XRT (except patients with parameningeal tumors with meningeal extension, who received XRT on day 0), IFOS/mesna weeks 9, 12, 16, and VCR weeks 9, 10, 11, 12, 16; weeks 20-99; IFOS/mesna q 3 weeks X 2, ETOP q 3 weeks X 2, and VCR weekly X 6 weeks. Four drug cycles were repeated every 9 weeks, beginning at week 29. In January 1991, the duration of therapy was reduced to 12 courses due to emerging evidence of IFOS-induced renal tubular dysfunction.Of the 62 patients evaluable for response, 45 (73%) achieved a complete response. There were three fatal toxicities due to infection. Life-threatening neutropenia was seen in 55 of 60 patients, and life-threatening infections occurred in 27 of 60 patients. Twenty-five patients (42%) developed some degree of neurotoxicity from vincristine. Eleven patients (18%) developed nephrotoxicity, 7 cases of which were severe; 6 of the 11 patients who developed nephrotoxicity were < 2 years old.This pilot study had toxicity and response rates comparable to the other two Intergroup Rhabdomyosarcoma Study (IRS)-IV pilot trials of vincristine-actinomycin-cyclophosphamide and vincristine-actinomycin-ifosfamide and is, therefore, being evaluated in the current IRS randomized trial. Due to the high incidence of life-threatening neutropenia and infections, the use of growth factors is now routine. Five of 11 patients who developed nephrotoxicity did so after more than eight courses of IFOS; therefore, the current randomized trial limits IFOS to a total of eight courses.

  View details for Web of Science ID A1997WX90000005

  View details for PubMedID 9149741

• Frequent and selective methylation of p15 and deletion of both p15 and p16 in T-cell acute lymphoblastic leukemia CANCER RESEARCH Batova, A., Diccianni, M. B., Yu, J. C., Nobori, T., Link, M. P., Pullen, J., Yu, A. L. 1997; 57 (5): 832-836

  Abstract

  Frequent deletion of chromosome 9p21 in many cancers has suggested the presence of tumor suppressor genes in this region. Two genes mapping to 9p21, p15 and p16, encode inhibitors for cyclin-dependent kinases 4 and 6. We recently found that in T-cell acute lymphoblastic leukemia (T-ALL), both the p15 and p16 genes are deleted at a high frequency, with p16 gene deletion occurring slightly more frequently than p15 gene deletion. We now show that in addition to deletion, the p15 gene is preferentially hypermethylated at a 5' CpG island, which has been shown previously to be associated with loss of transcription of this gene. The p15 gene was methylated in 38% (17 of 45) of T-ALL patients at diagnosis and in 22% (7 of 32) of patients at relapse. On the other hand, methylation of the p16 gene was a rare event, occurring in 4% (2 of 49) of patients at diagnosis and in none (0 of 30) at relapse. The overall rates of alteration occurring in at least one allele of the p15 gene is 84% at diagnosis and 88% at relapse. These rates are as high as, if not greater than, those for the p16 gene (80% at diagnosis and 74% at relapse). In fact, such alterations involve both alleles in the majority of samples: 76% for p15 and 67% for p16 at diagnosis. All together, more than one-half (56%) of T-ALL samples harbor alterations in both alleles of both p15 and p16. These results lend strong support for a role of both p15 and p16 as tumor suppressors in T-ALL.

  View details for Web of Science ID A1997WK89700011

  View details for PubMedID 9041181

• Altered expression of p53 and mdm-2 proteins at diagnosis is associated with early treatment failure in childhood acute lymphoblastic leukemia JOURNAL OF CLINICAL ONCOLOGY Marks, D. I., Kurz, B. W., Link, M. P., Ng, E., Shuster, J. J., Lauer, S. J., Carroll, D., Brodsky, I., Haines, D. S. 1997; 15 (3): 1158-1162

  Abstract

  To determine whether potential alteration in p53 function through p53 gene mutation or mdm-2 overexpression correlates with early treatment failure in childhood acute lymphoblastic leukemia (ALL).Diagnostic marrow samples from 34 children were analyzed for p53 gene alterations by western blot and SSCP/DNA sequence analysis and for mdm-2 overexpression by western blot analysis. These samples were derived from two groups of children with ALL: 17 good outcome patients who are in long-term continuous complete remission and 17 poor outcome patients who did not achieve a complete remission or relapsed within 6 months of achieving remission.Two children within the poor outcome group were found to have p53 gene mutations. Furthermore, five poor outcome patients were shown to have greater than 10-fold overexpression of mdm-2 protein compared with the mean level of mdm-2 protein measured in the good outcome group. Aberrant p53 protein expression was found in only one good outcome patient, whereas no good outcome children were found to have elevated levels (> 10-fold) of mdm-2 protein.We show for the first time that potential alteration in p53 function in childhood ALL is more common (P = .036) in cases of early treatment failure than in children who remain in long-term continuous remission.

  View details for Web of Science ID A1997WN19000039

  View details for PubMedID 9060559

• 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 BLOOD Rubnitz, J. E., Shuster, J. J., Land, V. J., Link, M. P., Pullen, J., Camitta, B. M., Pui, C. H., Downing, J. R., Behm, F. G. 1997; 89 (4): 1143-1146

  Abstract

  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.

  View details for Web of Science ID A1997WG79700003

  View details for PubMedID 9028935

• Use of an anti-ALK antibody in the characterization of anaplastic large-cell lymphoma of childhood 6th International Conference on Malignant Lymphoma Hutchison, R. E., Banki, K., Shuster, J. J., Barrett, D., Dieck, C., Berard, C. W., Murphy, S. B., Link, M. P., Pick, T. E., Laver, J., Schwenn, M., Mathew, P., Morris, S. W. OXFORD UNIV PRESS. 1997: 37–42

  Abstract

  Anaplastic lymphoma kinase (ALK) is a tyrosine kinase inappropriately expressed in lymphoid tissue involved by CD30+ anaplastic large-cell lymphoma (ALCL) with the translocation t(2;5)(p23;q35)(, which juxtaposes the nucleophosmin gene (NPM) with that encoding ALK, resulting in a hybrid (NPM-ALK) message.A polyclonal antibody against residues of the kinase portion of NPM-ALK (designated anti-ALK 11) was tested for clinical utility in paraffin sections of 44 cases of pediatric large-cell lymphoma (LCL) and 17 additional lymphoma cases, by streptavidin-biotin-alkaline phosphatase method.Nineteen of 20 CD30+ cases (the majority exhibiting anaplastic morphology) labeled with anti-ALK 11, and 5/28 CD30- cases were also ALK+ (3 T cells, 1 null cell, and 1 B cell). Sixteen of 17 B-cell pediatric LCLs were negative, as were 6/6 cases of Hodgkin's disease and 7/7 cases of adult B-cell lymphoma. In pediatric LCLs with adequate follow-up (24/44 ALK+), there was no significant association between ALK expression and two-year event-free survival, similar to the finding reported previously for CD30 expression in these cases.We conclude that the majority of pediatric CD30+ ALCLs show ALK overexpression, consistent with the presence of the t(2;5)-encoded NPM-ALK fusion, but that the clinical significance of this entity remains unproven.

  View details for Web of Science ID A1997XB82400008

  View details for PubMedID 9187427

• NCCN pediatric osteosarcoma practice guidelines. The National Comprehensive Cancer Network. Oncology (Williston Park, N.Y.) O'Reilly, R., Link, M., FLETCHER, B., Gebhardt, M., Krance, R., Meyers, P., Neff, J., Schwartz, C. 1996; 10 (12): 1799-?

  View details for PubMedID 8985965

• Preferential inactivation of p15(INK4B) but not p16(INK4A) by hypermethylation in T cell acute lymphoblastic leukemia. Yu, A. L., Batova, A., Diccianni, M. B., Pullen, J., Link, M. P., Yu, J. AMER SOC HEMATOLOGY. 1996: 1408–

  View details for Web of Science ID A1996VT98301408

• Improved survival for children with B-cell acute lymphoblastic leukemia and stage IV small noncleaved-cell lymphoma: A pediatric oncology group study JOURNAL OF CLINICAL ONCOLOGY Bowman, W. P., Shuster, J. J., Cook, B., Griffin, T., Behm, F., Pullen, J., Link, M., Head, D., Carroll, A., Berard, C., Murphy, S. 1996; 14 (4): 1252-1261

  Abstract

  In an effort to improve outcome for children with advanced B-cell malignancies, a treatment plan based on a published regimen that consists of four courses of fractionated cyclophosphamide (cyclo) given with doxorubicin (doxo) and vincristine (VCR) was intensified by alternating with sequential high-dose methotrexate (MTX) and cytarabine (Ara-C), given in conjunction with intrathecal (IT) MTX and Ara-C.From October 1986 to October 1992, 133 eligible patients were enrolled: 74 with B-cell (surface immunoglobulin-positive [Slg+] acute lymphoblastic leukemia (B-ALL) and 59 with stage IV small noncleaved-cell lymphoma (SNCCL). The median age was 8 years; there were 103 males and 30 females. Abdominal tumor masses were prominent in 63 cases (33 B-ALL and 30 stage IV SNCCL).Complete remission (CR) was achieved in 66 B-ALL and 57 stage IV patients (93% overall). At 4 years, the estimated event-free survival (EFS) rate is 65% +/- 8% for patients with B-ALL and 79% +/- 9% for those with stage IV SNCCL. Among patients with CNS involvement, 23 of 36 remain in CR (4-year EFS rate, 64% +/- 13%). Relapses occurred early; only 3 patients relapsed after completion of therapy. Thirteen relapses occurred in the marrow, three in the CNS, and six in other sites. Of 11 CNS-positive patients who relapsed, only two recurred primarily in the CNS.The results of this study indicate that with intensified chemotherapy an increasing potential for cure exists for patients with B-ALL and stage IV SNCCL.

  View details for Web of Science ID A1996UF06800027

  View details for PubMedID 8648381

• High incidence of potential p53 inactivation in poor outcome childhood acute lymphoblastic leukemia at diagnosis BLOOD Marks, D. I., Kurz, B. W., Link, M. P., Ng, E., Shuster, J. J., Lauer, S. J., Brodsky, I., Haines, D. S. 1996; 87 (3): 1155-1161

  Abstract

  Previous studies have indicated that p53 gene mutations were an uncommon event in acute lymphoblastic leukemia (ALL) in children. In one series of 330 patients, p53 mutations were seen in fewer than 3%. We analyzed bone marrow mononuclear cells derived from 10 children with ALL at diagnosis who subsequently failed to achieve a complete remission or who developed relapse within 6 months of attaining complete remission for p53 gene mutations and mdm-2 overexpression. We found that three children had p53 gene mutations, and four overexpressed mdm-2. Also, experiments comparing relative levels of mdm-2 RNA and protein in these patients demonstrated that mdm-2 overexpression can occur at the transcriptional and posttranscriptional level in primary leukemic cells. Although we were unable to link Waf-1 RNA expression with p53 status in childhood ALL, our data show potential p53 inactivation by multiple mechanisms in a large percentage of these patients and demonstrate that these alterations can be detected at diagnosis. Inactivation of the p53 pathway may, therefore, be important in children with ALL who fail to respond to treatment and may be useful for the early identification of children requiring alternative therapies.

  View details for Web of Science ID A1996TT48400040

  View details for PubMedID 8562942

• Uniform approach to risk classification and treatment assignment for children with acute lymphoblastic leukemia JOURNAL OF CLINICAL ONCOLOGY Smith, M., Arthur, D., Camitta, B., Carroll, A. J., Crist, W., Gaynon, P., Gelber, R., Heerema, N., Korn, E. L., Link, M., Murphy, S., Pui, C. H., Pullen, J., Reaman, G., Sallan, S. E., Sather, H., Shuster, J., Simon, R., Trigg, M., Tubergen, D., Uckun, F., Ungerleider, R. 1996; 14 (1): 18-24

  Abstract

  To define more uniform criteria for risk-based treatment assignment for children with acute lymphoblastic leukemia (ALL), the Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute (NCI) sponsored a workshop in September 1993. Participants included representatives from the Childrens Cancer Group (CCG), Pediatric Oncology Group (POG), Dana-Farber Cancer Institute (DFCI), St Jude Children's Research Hospital (SJCRH), and the CTEP.Workshop participants presented and reviewed data from ALL clinical trials, using weighted averages to combine outcome data from different groups.For patients with B-precursor (ie, non-T, non-B) ALL, the standard-risk category (4-year event-free survival [EFS] rate, approximately 80%) will include patients 1 to 9 years of age with a WBC count at diagnosis less than 50,000/microL. The remaining patients will be classified as having high-risk ALL (4-year EFS rate, approximately 65%). For patients with T-cell ALL, different treatment strategies have yielded different conclusions concerning the prognostic significance of T-cell immunophenotype. Therefore, some groups/institutions will classify patients with T-cell ALL as high risk, while others will assign risk for patients with T-cell ALL based on the uniform age/WBC count criteria. Workshop participants agreed that the risk category of a patient may be modified by prognostic factors in addition to age and WBC count criteria, and that a common set of prognostic factors should be uniformly obtained, including DNA index (DI), cytogenetics, early response to treatment (eg, day-14 bone marrow), immunophenotype, and CNS status.The more uniform approach to risk-based treatment assignment and to collection of specific prognostic factors should increase the efficiency of future ALL clinical research.

  View details for Web of Science ID A1996TP68700004

  View details for PubMedID 8558195

• Stage-specific expression of the HOXC4 homeobox gene during T and B cell ontogeny. Lawrence, H. J., Sauvageau, G., Kraft, D., Waller, N., LOPEZ, A. R., Link, M. P., Humphries, R. K., Largman, C. AMER SOC HEMATOLOGY. 1995: 1195–95

  View details for Web of Science ID A1995TH91001197

• STAGE-SPECIFIC AND LINEAGE-SPECIFIC EXPRESSION OF THE HOXA10 HOMEOBOX GENE IN NORMAL AND LEUKEMIC HEMATOPOIETIC-CELLS EXPERIMENTAL HEMATOLOGY Lawrence, H. J., Sauvageau, G., Ahmadi, N., LOPEZ, A. R., LEBEAU, M. M., Link, M., Humphries, K., Largman, C. 1995; 23 (11): 1160-1166

  Abstract

  There is growing evidence that the HOX homeobox-containing transcription factors are differentially expressed during hematopoiesis. We have previously demonstrated that the HOXA10 gene is expressed in unfractionated normal marrow and in immortalized leukemic cell lines with myelomonocytic features, but not in cell lines with lymphoid or erythroid features. To gain insights into the patterns of activation of this gene during hematopoietic differentiation, we have examined HOXA10 expression in CD34+ and CD34- subfractions of normal marrow and normal peripheral blood, as well as samples from patients with a variety of acute and chronic leukemias. HOXA10 is strongly expressed in CD34+ normal marrow cells, markedly downregulated in CD34- marrow cells, and inactive in mature neutrophils, monocytes, and lymphocytes. HOXA10 is expressed in all types of acute myelogenous leukemia (AML) with the notable exception of acute promyelocytic leukemia (AML-M3). HOXA10 message is observed in chronic myelogenous leukemia (CML) but appears to be reduced in accelerated phase and blast crisis, particularly lymphoid blast crisis. With rare exception, HOXA10 expression is not observed in samples of acute or chronic lymphoid leukemias. Normal marrow and patient samples appear to contain a single transcript which encodes a full-length homeobox-containing protein, while immortalized cell lines contain an additional alternatively spliced transcript. These studies indicate that HOXA10 expression is restricted to early stages of myeloid differentiation.

  View details for Web of Science ID A1995RX94700005

  View details for PubMedID 7556525

• B-CELL LINEAGE CONFERS A FAVORABLE OUTCOME AMONG CHILDREN AND ADOLESCENTS WITH LARGE-CELL LYMPHOMA - A PEDIATRIC-ONCOLOGY-GROUP STUDY JOURNAL OF CLINICAL ONCOLOGY Hutchison, R. E., Berard, C. W., Shuster, J. J., Link, M. P., Pick, T. E., Murphy, S. B. 1995; 13 (8): 2023-2032

  Abstract

  The goal of this study was to assess the immunophenotype of uniformly treated cases of pediatric large-cell non-Hodgkin's lymphoma (NHL) to determine the prognostic importance of B-cell and T-cell lineages and of CD30 positivity.Sixty-nine patients were analyzed by immunochemistry. All patients were classified histologically, staged in a uniform manner, and treated according to one of two protocols for localized (stage I and II) NHL or advanced (stage III and IV) large-cell NHL. Antibodies included anti-CD45, CD20, CD45Ra, MB-2 (not clustered), CD3, CD45Ro, CD43, CD15, CD30, and CD68. Statistical analysis used the exact conditional chi 2 and Kruskall-Wallace tests for clinical features and the log-rank test to evaluate event-free survival (EFS).Immunophenotypic results demonstrated 25 B-cell, 23 T-cell, and 21 indeterminate lineage. Twenty-seven patients expressed CD30 (17 T-cell and 10 indeterminate lineage), and of these, 22 showed histology of anaplastic large-cell lymphoma (ALCL). B-cell patients were older (P = .018) and showed more favorable survival than patients with T-cell or indeterminate lineage (96% EFS at 3 years, 96% v 67% and 74%, B v T and indeterminate lineage [P = .027]). B-cell lineage was seen more frequently in limited-stage patients, but was also associated with favorable survival when stratified for stage (P = .036). CD30 expression (P = .96) and ALCL histology (P = .90) did not show significant associations with survival.We conclude that among pediatric large-cell lymphomas, B-cell lineage is proportionately less frequent than in adults and CD30 antigen-expressing lymphomas are frequent among patients with T-cell and indeterminate lineage. B-cell phenotype tends to occur in older children and is associated with superior survival.

  View details for Web of Science ID A1995RM47300024

  View details for PubMedID 7636544

• SAFETY AND EFFICACY OF L-LEUCOVORIN RESCUE FOLLOWING HIGH-DOSE METHOTREXATE FOR OSTEOSARCOMA MEDICAL AND PEDIATRIC ONCOLOGY Goorin, A., Strother, D., Poplack, D., LETVAK, L. A., George, M., Link, M. 1995; 24 (6): 362-367

  Abstract

  High-dose methotrexate with leucovorin rescue (HDMTX-LCV) is an important component of regimens used in the treatment of osteosarcoma. As of this writing the commercially available form of leucovorin is a racemic mixture of d- and l-diastereoisomers; the l-isomer is the active component. This study describes the efficacy and safety of l-leucovorin in HDMTX-LCV regimens. Fifteen patients with osteosarcoma who were enrolled into or treated according to Pediatric Oncology Group protocols 8759 and 8651 received l-leucovorin (7.5 mg every 6 hours) in place of d,l-leucovorin following high-dose methotrexate. Safety data were collected for 1 week after each course or until any toxicities resolved. The mean number of l-leucovorin doses per course was 16.2 and the mean total dose per course was 126 mg. Adverse experiences were generally mild or moderate and occurred in 54 (60%) of 90 courses of l-leucovorin therapy. One l-leucovorin patients, who had inadequate methotrexate rescue, developed severe typhlitis. There were no instances of severe, acute methotrexate toxicity. Myelosuppression was seen but, in general, was not severe. These results support the conclusion that l-leucovorin effectively rescues patients from the toxicity of high-dose methotrexate.

  View details for Web of Science ID A1995QZ32900004

  View details for PubMedID 7715542

• TREATMENT OF OSTEOSARCOMA WITH IFOSFAMIDE - COMPARISON OF RESPONSE IN PEDIATRIC-PATIENTS WITH RECURRENT DISEASE VERSUS PATIENTS PREVIOUSLY UNTREATED - A PEDIATRIC-ONCOLOGY-GROUP STUDY MEDICAL AND PEDIATRIC ONCOLOGY Harris, M. B., Cantor, A. B., Goorin, A. M., Shochat, S. J., AYALA, A. G., Ferguson, W. S., Holbrook, T., Link, M. P. 1995; 24 (2): 87-92

  Abstract

  This study was designed to test if the activity of a phase II agent, ifosfamide, would have been underestimated if it was tested exclusively in a population of children and young adults with recurrent osteosarcoma. The response rate to ifosfamide was compared in patients younger than 30 years of age with previously untreated osteosarcoma with metastases at diagnosis and/or unresectable primary tumors (stratum 1) with that of patients with recurrent osteosarcoma following adjuvant chemotherapy who were not previously exposed to ifosfamide (stratum 2). Evaluation of response was conducted 3 weeks after two courses of ifosfamide (2400 mg/m2 x 5 days) were administered 3 weeks apart. Nine of 33 (27%) evaluable patients in stratum 1 responded (1 complete and 8 partial responses) to ifosfamide. Among 30 evaluable patients in stratum 2, only 3 (10%) responded (1 complete and 2 partial responses; P = .04) Both groups of patients received equal doses of ifosfamide and experienced comparable toxicities. Results from this study suggest that the activity of new agents will be underestimated if tested in a population of heavily pretreated patients with recurrent disease. When possible, new chemotherapeutic agents should be tested in patients with a poor prognosis who have not been exposed to chemotherapy.

  View details for Web of Science ID A1995QH46900004

  View details for PubMedID 7990769

• ABVD/MOPP AND LOW-DOSE INVOLVED-FIELD RADIOTHERAPY IN PEDIATRIC HODGKINS-DISEASE - THE STANFORD EXPERIENCE JOURNAL OF CLINICAL ONCOLOGY Hunger, S. P., Link, M. P., Donaldson, S. S. 1994; 12 (10): 2160-2166

  Abstract

  We reported previously that treatment with six cycles of mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) chemotherapy and 15 to 25 Gy irradiation was effective in curing children with Hodgkin's disease, but was associated with a 6.5% 10-year risk of development of secondary leukemia. Based on the results of that study, a successor study was designed with the objective to maintain treatment efficacy while decreasing adverse effects, particularly the occurrence of secondary leukemia.Fifty-seven children with a chronologic and/or bone age less than 16 years were enrolled onto this study between May 1982 and October 1990. Treatment consisted of six cycles of combination chemotherapy--three of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and three of MOPP--and low-dose irradiation (15 Gy) of involved fields. Boosts of 10 Gy were given to areas of bulky disease and to those that did not respond completely after two cycles of chemotherapy.With a median follow-up duration of 6.7 years, the projected 10-year survival and event-free survival (EFS) rates are 96% (SE 2.5%) and 93% (SE 3.5%) for the entire cohort of 57 patients, and 85% (SE 10%) and 69% (SE 12.8%), respectively, for 13 patients with stage IV disease. No patient has developed a second malignancy. Growth and development have progressed normally. No patients have symptomatic cardiac, pulmonary, or thyroid disease. Subclinical abnormalities of pulmonary function were detected in 32% and chemical hypothyroidism in 16%.This therapy was highly efficacious in children with Hodgkin's disease without unacceptable toxicity. Future efforts should be directed toward further reducing therapy for favorable early-stage patients and improving treatment efficacy for those with stage IV disease.

  View details for Web of Science ID A1994PL36300023

  View details for PubMedID 7523608

• HYPNOSIS IN THE PREVENTION OF CHEMOTHERAPY-RELATED NAUSEA AND VOMITING IN CHILDREN - A PROSPECTIVE-STUDY JOURNAL OF DEVELOPMENTAL AND BEHAVIORAL PEDIATRICS JACKNOW, D. S., Tschann, J. M., Link, M. P., Boyce, W. T. 1994; 15 (4): 258-264

  Abstract

  To study the effectiveness of hypnosis for decreasing antiemetic medication usage and treatment of chemotherapy-related nausea and vomiting in children with cancer, we conducted a prospective, randomized, and controlled single-blind trial in 20 patients receiving chemotherapy for treatment of cancer. Patients were randomized to either hypnosis or standard treatment. The hypnosis group used hypnosis as primary treatment for nausea and vomiting, using antiemetic medication on a supplemental (p.r.n.) basis only, whereas the control group received a standardized antiemetic medication regimen. Nausea, vomiting, and p.r.n. antiemetic medication usage were measured during the first two courses of chemotherapy. Anticipatory nausea and vomiting were assessed at 1 to 2 and 4 to 6 months postdiagnosis. Patients in the hypnosis group used less p.r.n antiemetic medication than control subjects during both the first (p < .04) and second course of chemotherapy (p < .02). The two groups did not differ in severity of nausea and vomiting. The hypnosis group experienced less anticipatory nausea than the control group at 1 to 2 months postdiagnosis (p < .02). Results suggest self-hypnosis is effective for decreasing antiemetic medication usage and for reducing anticipatory nausea during chemotherapy.

  View details for Web of Science ID A1994PC01100006

  View details for PubMedID 7798371

• FREQUENCY AND PROGNOSTIC-SIGNIFICANCE OF HRX REARRANGEMENTS IN INFANT ACUTE LYMPHOBLASTIC-LEUKEMIA - A PEDIATRIC-ONCOLOGY-GROUP STUDY BLOOD Rubnitz, J. E., Link, M. P., Shuster, J. J., Carroll, A. J., Hakami, N., Frankel, L. S., Pullen, D. J., Cleary, M. L. 1994; 84 (2): 570-573

  Abstract

  Chromosome band 11q23, the location of the HRX gene, is a site of recurrent translocations in human malignancies. Infants with acute lymphoblastic leukemia (ALL) commonly have 11q23 translocations and have an especially poor prognosis despite intensive chemotherapy. We analyzed 96 cases of infant ALL treated on three consecutive Pediatric Oncology Group protocols to determine the frequency and prognostic significance of molecular rearrangements of HRX. Overall, 78 cases (81%) had HRX rearrangements detected by Southern blot analysis performed with a single HRX cDNA probe, whereas 18 cases (19%) had germline HRX. Of the 78 cases with HRX rearrangements, only 50 had abnormalities of 11q23 detected cytogenetically. Molecular abnormalities of HRX were associated with early treatment failure and a very poor outcome. Estimated event-free survival for patients with HRX rearrangements was 19% (SE, 7%) at 3 years, compared with 46% (SE, 17%) for patients with germline HRX (P = .033 by the two-sided logrank test). Therefore, infants with ALL and molecular abnormalities of HRX represent a group with an extremely high rate of failure who clearly need innovative or experimental treatment. Furthermore, cytogenetic analysis alone failed to detected 36% of HRX rearrangements, suggesting that molecular analysis be performed on all infants with ALL to identify this group of high-risk patients.

  View details for Web of Science ID A1994NX15400028

  View details for PubMedID 8025282

• SIMULTANEOUS EXPRESSION OF RBTN-2 AND BCR-ABL ONCOGENES IN A T-ALL WITH A T(1114)(P13Q11) AND A LATE-APPEARING PHILADELPHIA-CHROMOSOME LEUKEMIA Fizzotti, M., CHEN, E. Y., Link, M. P., Carroll, A. J., Foroni, L., Rabbitts, T. H., Crist, W. M., Clark, S. S. 1994; 8 (7): 1124-1130

  Abstract

  Cytogenetic analysis of a pediatric patient with T-cell acute lymphoblastic leukemia (T-ALL) revealed a mosaic karyotype, 47,XX,+17,t(11;14)(p13;q11)/47,XX,+17,t(9;22)(q34;q11),t(11;14) (p13;q11). DNA blot analysis was used to examine the break-point within the BCR gene on chromosome 22 and showed that the breakpoint occurred within the 20-kb minor breakpoint cluster region (m-bcr) located within the first intron of the BCR gene. Immunoprecipitation analysis demonstrated that the leukemic cells expressed the P185 BCR-ABL protein tyrosine kinase. P185 BCR-ABL has previously been shown to be expressed in most cases of Ph+ acute leukemia of myeloid and B-progenitor origin. Here, we demonstrate for the first time that P185 can also be expressed in the T-cell lineage. DNA blot hybridization was also used to characterize the t(11;14) translocation. This showed rearrangement on chromosome 11 within the T-ALLbcr region, upstream of the RBTN-2 gene. Polymerase chain reaction revealed the presence of RBTN-2 transcripts in the leukemic cells. Finally, comparison of the T-ALLbcr, BCR-ABL, IGH, TCR beta and gamma gene rearrangements in leukemic cells obtained at the time of diagnosis and at first relapse showed that relapse occurred in a leukemic clone indistinguishable from the major Ph+ clone involved at diagnosis. Together, these data support a multistep pathogenesis in which the Philadelphia (Ph) chromosome translocation appeared subsequent to the +17 and t(11;14) and imparted a growth advantage over the Ph-negative cells that carried these abnormalities.

  View details for Web of Science ID A1994NZ72300006

  View details for PubMedID 8035604

• PRESENTING CHARACTERISTICS OF TRISOMY-8 AS THE PRIMARY CYTOGENETIC ABNORMALITY ASSOCIATED WITH CHILDHOOD ACUTE LYMPHOBLASTIC-LEUKEMIA - A PEDIATRIC-ONCOLOGY-GROUP (POG) STUDY-(8600/8493) CANCER GENETICS AND CYTOGENETICS Pettenati, M. J., Rao, N., Wofford, M., Shuster, J. J., Pullen, D. J., Ling, M. P., Steuber, C. P., Carroll, A. J. 1994; 75 (1): 6-10

  Abstract

  Although trisomy 8 is the single most common numerical abnormality in acute myeloid leukemia (AML), relatively few cases with acute lymphoblastic leukemia (ALL) and trisomy 8 have been reported. We report the clinical and laboratory features of seven children with ALL and trisomy 8 as the sole cytogenetic abnormality and review nine similar cases from the literature. Among the children studied by the Pediatric Oncology Group (POG) with newly diagnosed ALL, only 0.3% had trisomy 8 as the sole abnormality. Four of our patients had T-cell ALL and three had early pre-B ALL. Presenting clinical features were typical for the respective immunophenotypes. Six of the seven children achieved complete remission. Our study suggest that trisomy 8 is an infrequent, recurring abnormality among children with ALL, which appears to be associated with a T-cell immunophenotype.

  View details for Web of Science ID A1994NZ61500002

  View details for PubMedID 8039165

• MIC2 ANALYSIS IN PEDIATRIC LYMPHOMAS AND LEUKEMIAS HUMAN PATHOLOGY Riopel, M., Dickman, P. S., Link, M. P., Perlman, E. J. 1994; 25 (4): 396-399

  Abstract

  Monoclonal antibodies to the glycoprotein product of the MIC2 gene strongly and reliably stain primitive neuroectodermal tumors and Ewing's sarcomas, and are negative in neuroblastomas and most rhabdomyosarcomas. Therefore, these antibodies are helpful in the diagnosis of small round cell tumors of childhood (SRCT). Lymphomas also are in the differential diagnosis of SRCT, but few have been studied with respect to MIC2 protein expression. In the present study we used the 12E7 antibody to assess MIC2 expression in 82 pediatric non-Hodgkin's lymphomas. Forty lymphoblastic, 22 small noncleaved, and 20 large cell lymphomas were studied. Strong immunoreactivity was found in 37 of the 40 (93%) lymphoblastic lymphomas, whereas only one of the 22 (5%) small noncleaved lymphomas was 12E7 positive. Four of the 20 (20%) large cell lymphomas also were immunoreactive. Three 12E7+ lymphoblastic lymphomas were primary in bone and were of B-progenitor lineage; Ewing's sarcoma was included in the initial differential diagnosis of these cases. Evaluation of 125 pediatric acute lymphocytic leukemia (ALL) cases for MIC2 expression showed similar results, with all 36 T-cell ALLs showing strong expression, one of eight B-cell (Burkitt-like) ALLs showing 12E7 expression, and 62 of 81 B-progenitor ALLs showing 12E7 positivity. We conclude that among the SRCTs, MIC2 expression is not limited to Ewing's sarcoma and primitive neuroectodermal tumors, but also shows strong and reliable expression in lymphoblastic lymphomas and related leukemias. MIC2 analysis continues to be helpful in the diagnosis of SRCT, provided that a panel of antibodies is used. In addition, the possibility that MIC2 analysis may aid in the distinction of lymphoblastic lymphomas from small noncleaved lymphomas needs to be further addressed.

  View details for Web of Science ID A1994NL05600012

  View details for PubMedID 8163272

• EWINGS-SARCOMA - ROUTINE DIAGNOSTIC UTILIZATION OF MIC2 ANALYSIS - A PEDIATRIC-ONCOLOGY-GROUP CHILDRENS-CANCER-GROUP INTERGROUP STUDY HUMAN PATHOLOGY Perlman, E. J., Dickman, P. S., Askin, F. B., Grier, H. E., Miser, J. S., Link, M. P. 1994; 25 (3): 304-307

  Abstract

  Ewing's sarcoma and peripheral neuroectodermal tumor (PNET) are small blue cell tumors with no reliable positive diagnostic markers. However, Ewing's sarcoma and PNET recently have been shown to strongly express an antigen determined by the MIC2 gene, whereas other blue cell tumors of childhood for the most part do not. MIC2 analysis therefore offers a distinctive addition to the panel of immunohistochemical stains used to differentiate among small blue cell tumors of childhood, since it represents the first positive marker for Ewing's sarcoma and PNET. This study addresses the reliability of MIC2 analysis using the monoclonal antibody 12E7 on tumors registered in the current Intergroup Ewing's Sarcoma protocol. Of 244 tumors, 221 (91%) showed a diffuse strong membranous pattern. The antibody appears to withstand all the fixation variables inherent in a multi-institutional study. We conclude that MIC2 expression is highly reliable as a positive marker for the Ewing's sarcoma/PNET family of tumors when the results are interpreted in the total context with clinical and pathologic parameters.

  View details for Web of Science ID A1994NF07200014

  View details for PubMedID 8150461

• HODGKINS-DISEASE IN THE VERY YOUNG 34th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology Cleary, S. F., Link, M. P., Donaldson, S. S. PERGAMON-ELSEVIER SCIENCE LTD. 1994: 77–83

  Abstract

  A retrospective review of patients with Hodgkin's disease treated at Stanford University Medical Center was undertaken to determine if, within the pediatric population, children < or = 10 years of age have a unique prognosis and response to treatment.Records of all patients treated for Hodgkin's disease at SUMC between 1961 and 1991 were reviewed.Of 2238 patients with Hodgkin's disease, 91 (4%) were < or = 10 years of age. There is a predominance of male patients (80%) and a higher percentage of mixed cellularity (33%) and lymphocyte predominance (13%) histologies among the very young patients compared to adolescents and adults. The 5 and 10-year survival is 94 +/- 3% and 92 +/- 3%, respectively, for children < or = 10 vs. 93 +/- 2% and 86 +/- 3% for adolescents and 84 +/- 1% and 73 +/- 1% for adults. Five and 10-year freedom from relapse is also higher in the youngest children (88 +/- 4% and 85 +/- 4%, respectively) compared to adolescents (78 +/- 3% and 74 +/- 3%, respectively) and adults (70 +/- 1% and 67 +/- 1%, respectively). Actuarial survival at 25 years for children < or = 10 years is 78%, which is slightly better than for adolescents (67%) and significantly better than for adults (41%) (p = 0.001). Actuarial 25-year freedom from relapse is also significantly better for children < or = 10 (78%) compared to adolescents (74% [p = 0.05]) and adults (65% [p = 0.001]). For all stages of disease, children < or = 10 fare similarly to or slightly better than adolescents and substantially better than adults. For those with Stage I or II disease, survival at 5, 10, and 25 years is 98 +/- 2%, 93 +/- 4% and 73%, respectively, for children aged < or = 10; 98 +/- 1%, 91 +/- 3%, and 79%, respectively, for adolescents and 89 +/- 1%, 80 +/- 1%, and 45%, respectively, for adults. The greatest difference between age groups is seen for Stage III and IV patients. Those aged < or = 10 have an 89 +/- 5% 5 and 10-year survival, and 89% actuarial 25-year survival compared to 87 +/- 4%, 80 +/- 5%, and 28%, respectively, for adolescents and 77 +/- 2%, 64 +/- 2%, and 41%, respectively, for adults. Of patients < or = 10 years of age, 28 (31%) were treated with primary external beam radiotherapy, and 59 (65%) received combined modality therapy consisting of low-dose radiation and chemotherapy. With a median follow-up of 11 years, freedom from relapse is 64% and survival 75% for the radiotherapy group, compared to 97% (p = 0.000) and 93% (p = 0.21) for those treated with combined modality therapy.Results indicate that young age is a favorable prognostic factor in Hodgkin's disease. Combined modality therapy has led to improved freedom from relapse and survival rates for all stages of disease and is currently the treatment of choice for the majority of very young children.

  View details for Web of Science ID A1994MP35300010

  View details for PubMedID 7505777

• SECONDARY BREAST-CANCER IN PATIENTS PRESENTING WITH OSTEOSARCOMA - POSSIBLE INVOLVEMENT OF GERMLINE P53 MUTATIONS MEDICAL AND PEDIATRIC ONCOLOGY Russo, C. L., McIntyre, J., Goorin, A. M., Link, M. P., Gebhardt, M. C., Friend, S. H. 1994; 23 (4): 354-358

  Abstract

  Second malignancies following treatment for osteosarcoma are unusual. Breast cancer occurring in patients with osteosarcoma has been reported following therapeutic chest irradiation. We now report three cases of breast cancer occurring in young women who were successfully treated for osteosarcoma. These women had not received therapeutic chest irradiation and in two of the three women there was no family history of breast cancer. Peripheral blood was available for study from one case. Of import, this case demonstrated a germline mutation in exon 7 of the tumor suppressor gene, p53. The mutation was detected by constant denaturing gradient gel electrophoresis and confirmed by DNA sequencing. In this particular patient, inactivation of the p53 gene may be involved in the development of both the first and second malignancy.

  View details for Web of Science ID A1994PD28400006

  View details for PubMedID 8058007

• IMMUNOCYTOCHEMICAL STUDY OF 12E7 IN SMALL ROUND-CELL TUMORS OF CHILDHOOD - AN ASSESSMENT OF ITS SENSITIVITY AND SPECIFICITY HISTOPATHOLOGY Ramani, P., Rampling, D., Link, M. 1993; 23 (6): 557-561

  Abstract

  12E7 is a monoclonal antibody to the MIC2 gene product and can be applied to formalin-fixed, paraffin-embedded tissue. The diagnostic utility of 12E7 as a marker of Ewing's sarcoma and peripheral neuroectodermal tumour was assessed. Immunocytochemical studies were performed on 120 small round-cell tumours from children and adolescents. Immunoreactivity for 12E7 was seen in 13 of 15 Ewing's sarcomas. 14 of 15 peripheral neuroectodermal tumours, four of 14 embryonal rhabdomyosarcoma, seven of 11 T-lymphoblastic lymphomas and one T-cell acute lymphoblastic leukaemia. Immunoreactivity was located on the cell-membrane of Ewing's sarcomas, peripheral neuroectodermal tumours and lymphoid tumours while rhabdomyosarcomas showed weak, cytoplasmic staining in differentiated rhabdomyoblasts. Studies on alveolar rhabdomyosarcomas (n = 10), acute myeloid leukaemias (3), B-lymphoblastic lymphomas (8), blastema-rich nephroblastomas (9), neuroblastomas (20) and retinoblastomas (10) as well as single examples of B-cell acute lymphoblastic leukaemia, Ki-1 anaplastic lymphoma of indeterminate phenotype and intra-abdominal desmoplastic tumour with divergent differentiation were negative. 12E7 is a sensitive marker for the Ewing's sarcoma/peripheral neuroectodermal group of tumours and is useful in distinguishing them from neuroblastoma and blastema-rich nephroblastoma. However, immunopositivity for 12E7 should be interpreted in conjunction with the results of neural and lymphoid markers.

  View details for Web of Science ID A1993MN34600008

  View details for PubMedID 8314240

• DETECTION OF THE (11 22)(Q24 Q12) TRANSLOCATION OF EWINGS-SARCOMA AND PERIPHERAL NEUROECTODERMAL TUMOR BY REVERSE TRANSCRIPTION-POLYMERASE CHAIN-REACTION AMERICAN JOURNAL OF PATHOLOGY Downing, J. R., Head, D. R., Parham, D. M., Douglass, E. C., HULSHOF, M. G., Link, M. P., MOTRONI, T. A., Grier, H. E., CURCIOBRINT, A. M., Shapiro, D. N. 1993; 143 (5): 1294-1300

  Abstract

  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.

  View details for Web of Science ID A1993MF65600009

  View details for PubMedID 8238248

• HRX INVOLVEMENT IN DENOVO AND SECONDARY LEUKEMIAS WITH DIVERSE CHROMOSOME 11Q23 ABNORMALITIES BLOOD Hunger, S. P., Tkachuk, D. C., Amylon, M. D., Link, M. P., Carroll, A. J., WELBORN, J. L., Willman, C. L., Cleary, M. L. 1993; 81 (12): 3197-3203

  Abstract

  Chromosome band 11q23 is a site of recurrent translocations and interstitial deletions in human leukemias. Recent studies have shown that the 11q23 gene HRX is fused to heterologous genes from chromosomes 4 or 19 after t(4;11)(q21;q23) and t(11;19)(q23;p13) translocations to create fusion genes encoding proteins with structural features of chimeric transcription factors. In this report, we show structural alterations of HRX by conventional Southern blot analyses in 26 of 27 de novo leukemias with cytogenetically diverse 11q23 abnormalities. The sole case that lacked HRX rearrangements was a t(11;17)-acute myeloid leukemia with French-American-British M3-like morphology. We also analyzed 10 secondary leukemias that arose after therapy with topoisomerase II inhibitors and found HRX rearrangements in 7 of 7 with 11q23 translocations, and in 2 of 2 with unsuccessful karyotypes. In total, we observed HRX rearrangements in 35 leukemias involving at least nine distinct donor loci (1q32, 4q21, 6q27, 7p15, 9p21-24, 15q15, 16p13, and two 19p13 sites). All breakpoints localized to an 8-kb region that encompassed exons 5-11 of HRX, suggesting that fusion proteins containing similar portions of HRX may be consistently created in leukemias with 11q23 abnormalities. We conclude that alteration of HRX is a recurrent pathogenetic event in leukemias with 11q23 aberrations involving many potential partners in a variety of settings including acute myeloid leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia in blast crisis, and topoisomerase II inhibitor-induced secondary leukemias of both the myeloid and lymphoid lineages.

  View details for Web of Science ID A1993LG65900005

  View details for PubMedID 8389614

• ACUTE HYPERSENSITIVITY REACTIONS TO ETOPOSIDE IN A VEPA REGIMEN FOR HODGKINS-DISEASE JOURNAL OF CLINICAL ONCOLOGY Hudson, M. M., Weinstein, H. J., Donaldson, S. S., Greenwald, C., Kun, L., Tarbell, N. J., HUMPHREY, W. A., Rupp, C., Marina, N. M., Wilimas, J., Link, M. P. 1993; 11 (6): 1080-1084

  Abstract

  We report an unexpectedly high incidence of hypersensitivity to etoposide among 45 patients with newly diagnosed Hodgkin's disease treated with vinblastine, etoposide, prednisone, and doxorubicin (VEPA) plus radiation.Twenty-three of 45 patients (51%) had one or more acute hypersensitivity reactions to etoposide administration. The 23 patients were 8 to 18 years of age (median, 15 years); 12 were males. Four patients had experienced prior allergic reactions to antibiotics or intravenous contrast media.Hypersensitivity reactions followed the first or second dose of VEPA in most cases. The reactions occurred at a median time of 5 minutes (range, 3 to 120) from the start of the etoposide infusion. Fifteen patients reacted early (within 10 minutes), four midway through the infusion, and four after completion of the infusion. Signs and symptoms included flushing, respiratory problems, changes in blood pressure, and abdominal pain with or without nausea and vomiting. Respiratory problems included dyspnea, chest pain/tightness, bronchospasm, and cyanosis. Symptoms were alleviated by discontinuing the etoposide infusions and administering diphenhydramine and/or hydrocortisone; epinephrine was required to reverse bronchospasm in three cases. All 23 patients recovered without adverse sequelae and were rechallenged with etoposide. Fifteen patients tolerated subsequent etoposide infused at a slower rate, with antihistamine and/or corticosteroid premedication; five had recurrent hypersensitivity despite these measures. Three of these five developed similar symptoms when teniposide was substituted for etoposide. Three patients who had isolated episodes of hypotension on completion of the etoposide infusion successfully received subsequent infusions without premedication or change in infusion rate or concentration.Despite this unexpectedly high incidence of hypersensitivity among Hodgkin's disease patients treated with etoposide, rechallenge with the drug was successful in 78% of cases.

  View details for Web of Science ID A1993LF31000011

  View details for PubMedID 8501494

• LABORATORY CLINICAL INTERFACE WORKSHOP ON CHILDREN WITH CANCER Link, M. P., Stevens, J., Friend, S. H., Israel, M. A., Knudson, A. G., Sondel, P. M. WILEY-BLACKWELL. 1993: 3219–21

  View details for Web of Science ID A1993LD57000008

  View details for PubMedID 8490857

• 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 BLOOD Bash, R. O., Crist, W. M., Shuster, J. J., Link, M. P., Amylon, M., Pullen, J., Carroll, A. J., Buchanan, G. R., SMITH, R. G., Baer, R. 1993; 81 (8): 2110-2117

  Abstract

  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.

  View details for Web of Science ID A1993KY00500018

  View details for PubMedID 8471769

• A SERINE PROLINE-RICH PROTEIN IS FUSED TO HRX IN T(4-11) ACUTE LEUKEMIAS BLOOD Morrissey, J., Tkachuk, D. C., MILATOVICH, A., FRANCKE, U., Link, M., Cleary, M. L. 1993; 81 (5): 1124-1131

  Abstract

  Translocations involving chromosome band 11q23 in acute leukemias have recently been shown to involve the HRX gene that codes for a protein with significant similarity to Drosophila trithorax. HRX gene alterations are consistently observed in t(4;11) (q21;q23)-carrying leukemias and cell lines by Southern blot analyses and are accompanied by HRX transcripts of anomalous size on Northern blots. HRX-homologous cDNAs were isolated from a library prepared from t(4;11)-carrying acute leukemia cells. cDNAs representative of transcription products from the derivative 11 chromosome were shown to contain HRX sequences fused to sequences derived from chromosome band 4q21. Fragments of the latter were used to clone and analyze cDNAs for wild-type 4q21 transcripts that predicted a 140-Kd basic protein (named FEL) that is rich in prolines, serines, and charged amino acids. FEL contains guanosine triphosphate-binding and nuclear localization consensus sequences and uses one of two possible 5' exons encoding the first 12 or 5 amino acids. After t(4;11) translocations, 913 C-terminal amino acids of FEL are fused in frame to the N-terminal portion of HRX containing its minor groove DNA binding motifs. These features are similar to predicted t(11;19) fusion proteins, suggesting that HRX consistently contributes a novel DNA-binding motif to at least two different chimeric proteins in acute leukemias.

  View details for Web of Science ID A1993KP97700002

  View details for PubMedID 8443374

• The multi-institutional osteosarcoma study: an update. Cancer treatment and research Link, M. P. 1993; 62: 261-267

  View details for PubMedID 7682087

• Osteosarcoma in adolescents and young adults: new developments and controversies. Commentary on the use of presurgical chemotherapy. Cancer treatment and research Link, M. P. 1993; 62: 383-385

  View details for PubMedID 8096755

• LANGERHANS CELL HISTIOCYTOSIS PRESENTING WITH THE SUPERIOR VENA-CAVA SYNDROME - A CASE-REPORT MEDICAL AND PEDIATRIC ONCOLOGY Mogul, M., HARTMAN, G., Donaldson, S., Gelb, A., Link, M., Amylon, M., Glader, B. 1993; 21 (6): 456-459

  Abstract

  A case of Langerhans' cell histiocytosis confined to the mediastinum and presenting with de novo superior cava syndrome is reported. The causes of superior vena cava syndrome in childhood are discussed as is the importance of obtaining pathologic diagnosis prior to initiating therapy.

  View details for Web of Science ID A1993LK60200013

  View details for PubMedID 8515729

• A STUDY OF TOXICITY AND COMPARATIVE THERAPEUTIC EFFICACY OF VINDESINE-PREDNISONE VS VINCRISTINE-PREDNISONE IN CHILDREN WITH ACUTE LYMPHOBLASTIC-LEUKEMIA IN RELAPSE - A PEDIATRIC ONCOLOGY GROUP-STUDY INVESTIGATIONAL NEW DRUGS Vats, T., Buchanan, G., Mehta, P., Ragab, A., HVIZDALE, E., Nitschke, R., Link, M., Beardsley, G. P., MAYBEE, D., Krischer, J. 1992; 10 (3): 231-234

  Abstract

  Vindesine (des-acetyl Vinblastine) is a synthetic derivative of vinblastine, and was produced with the hope that it would have less neurotoxicity and hematopoietic toxicity than other vinca alkaloids. Phase I and II studies also demonstrated significant activity in lymphoid malignancies, especially Acute Lymphoblastic Leukemia (ALL). The present study was designed to compare therapeutic effectiveness of twice weekly vindesine (2 mg/M2/dose) plus Prednisone (60 mg/M2/dose) (Treatment 1) to weekly Vincristine (2 mg/M2/dose) plus Prednisone (60 mg/M2/day) (Treatment 2). All patients were less than 21 years of age, and had documented bone marrow relapse (blast count > 25%). In 39 patients presumed sensitive to vincristine, there were 11 complete responses out of 20 patients (55%) randomized to receive vindesine/prednisone and 7 complete responses out of 19 patients (37%) treated with Vincristine/Prednisone. In 37 patients resistant to vincristine, there were 7 complete responses (19%). Vindesine was more toxic than Vincristine. Major toxicities of vindesine included paraesthesias, peripheral neuropathy and ileus. Vindesine hematological toxicity appeared greater, but such toxicity is hard to assess in patients with bone marrow disease. In this study, vindesine and vincristine had similar efficacy, but vindesine use was associated with more toxicity.

  View details for Web of Science ID A1992JX01000015

  View details for PubMedID 1428733

• CHILDHOOD MALIGNANT NON-HODGKIN LYMPHOMAS OF UNCOMMON HISTOLOGY LEUKEMIA Ribeiro, R. C., Pui, C. H., Murphy, S. B., Shuster, J. J., HVIZDALA, E. V., FALLETTA, J., Link, M. P., Sullivan, M. P., Pick, T. E., Sandlund, J. T., Fairclough, D., Crist, W. M., Berard, C. W. 1992; 6 (8): 761-765

  Abstract

  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.

  View details for Web of Science ID A1992JJ50700003

  View details for PubMedID 1640726

• MORPHOLOGICAL, IMMUNOLOGICAL AND CYTOGENETIC STUDIES IN CHILDREN WITH ACUTE LYMPHOBLASTIC-LEUKEMIA AT DIAGNOSIS AND RELAPSE - A PEDIATRIC ONCOLOGY GROUP-STUDY LEUKEMIA Abshire, T. C., Buchanan, G. R., Jackson, J. F., Shuster, J. J., Brock, B., Head, D., Behm, F., Crist, W. M., Link, M., Borowitz, M., Pullen, D. J. 1992; 6 (5): 357-362

  Abstract

  The morphologic, immunologic and cytogenetic features of leukemic cells obtained at the time of first bone marrow relapse were compared with those obtained at initial diagnosis in 287 children with acute lymphoblastic leukemia (ALL) who were entered consecutively in a laboratory classification study of the Pediatric Oncology Group (POG). L1 to L2 shifts in French-American-British morphologic subtype were more common than the reverse (81/178 versus 15/61, p less than 0.001). A small but marginally significant number of cases acquired cytoplasmic granules at relapse, and 50 cases underwent a shift in periodic acid-Schiff reactivity that slightly favoured positive to negative. Shifts in immunophenotype were relatively rare, although shifts in cases with a pre-B phenotype to early pre-B ALL or vice versa occurred in about a third of pre-B cases. Loss of HLA-DR or the common ALL antigen occurred in 20 and 11% of cases, respectively. Of the 116 cases with analyzable karyotypes at diagnosis and relapse, 36 (31%) showed a change in karyotypes at relapse, usually from normal to pseudodiploid or hyperdiploid. Cytogenetic evidence for the emergence of a new clone after initial diagnosis was found in only one case. Analysis of the correlation of clinical and lymphoblast biologic features with event-free survival after an initial marrow relapse failed to demonstrate any prognostic significance for the changes identified in this study. T-cell immunophenotype proved to be the only factor significantly related to the outcome of retrieval therapy.

  View details for Web of Science ID A1992JB14100001

  View details for PubMedID 1534389

• ISOCHROMOSOMES IN CHILDHOOD ACUTE LYMPHOBLASTIC-LEUKEMIA - A COLLABORATIVE STUDY OF 83 CASES BLOOD Pui, C. H., Carroll, A. J., Raimondi, S. C., Schell, M. J., Head, D. R., Shuster, J. J., Crist, W. M., Borowitz, M. J., Link, M. P., Behm, F. G., Steuber, C. P., Land, V. J. 1992; 79 (9): 2384-2391

  Abstract

  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.

  View details for Web of Science ID A1992HW88400027

  View details for PubMedID 1571550

• PROGRESS AGAINST CHILDHOOD-CANCER - THE PEDIATRIC ONCOLOGY GROUP EXPERIENCE PEDIATRICS Vietti, T. J., Land, V., Shuster, J. J., Amylon, M., Link, M., Berard, C., Crist, W., Borowitz, M., FALLETTA, J., Bowman, W. P., Brecher, M., Castleberry, R., Frankel, L., Goorin, A., Hayes, F. A., Hvizdala, E., Krischer, J. P., Pollock, B. H., McWilliams, N., Murphy, S., Pick, T., Pullen, J., Ravindranath, Y., Smith, E. I., Steuber, C. P., Sullivan, M., VANEYS, J., Wharam, M. 1992; 89 (4): 597-600

  Abstract

  The sequential outcome was evaluated for all childhood cancers in which the Pediatric Oncology Group has conducted a series of clinical trials, with constant eligibility, on patients with newly diagnosed cancer. The analysis was applied to more than 7000 patients with cancer diagnosed between 1976 and 1989. These include acute leukemia (4 subgroups), non-Hodgkins lymphoma (4 subgroups), osteogenic sarcoma, and advanced neuroblastoma. In 8 of these 10 disease areas, significant improvement in outcome has occurred. In rare diseases such as pediatric cancer, collaborative studies may be the only way to conduct therapeutic trials of sufficient statistical power. A cooperative group has distinct advantages over a series of ad hoc collaborative studies in that it can maintain a unified data base, study its history with minimal confounding effects of changing institutional participants, and develop long-term research relationships among its participants.

  View details for Web of Science ID A1992HM25100004

  View details for PubMedID 1557237

• INTENSIVE SEQUENTIAL CHEMOTHERAPY FOR CHILDREN WITH ACUTE MYELOGENOUS LEUKEMIA - VAPA, 80-035, AND HI-C-DAZE 5TH INTERNATIONAL SYMP ON THERAPY OF ACUTE LEUKEMIAS Grier, H. E., Gelber, R. D., Link, M. P., CAMITTA, B. P., Clavell, L. A., WEISTEIN, H. J. NATURE PUBLISHING GROUP. 1992: 48–51

  Abstract

  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.

  View details for Web of Science ID A1992HX75100013

  View details for PubMedID 1374493

• CURRENT RESULTS OF STUDIES OF IMMUNOPHENOTYPE-BASED, AGE-BASED AND LEUKOCYTE-BASED THERAPY FOR CHILDREN WITH ACUTE LYMPHOBLASTIC-LEUKEMIA 5TH INTERNATIONAL SYMP ON THERAPY OF ACUTE LEUKEMIAS Crist, W., Shuster, J., Look, T., Borowitz, M., Behm, F., Bowman, P., Frankel, L., Pullen, J., Krance, R., Steuber, P., Camitta, B., Amylon, M., Link, M., Land, V. NATURE PUBLISHING GROUP. 1992: 162–166

  Abstract

  From February 1986 to January 1991 the Pediatric Oncology Group (POG) treated 2404 children or adolescents with acute lymphoblastic leukemia (ALL) on immunophenotype (T-, B-, Pre-B, or Early pre-B-cell), age, and leukocyte count based treatment protocols (ALinC 14, T-cell 3, B-cell and infant leukemia studies). The immunophenotypic subgroups comprised 78.9% B-precursor cell, 15.1% T-cell, 2.0% B-cell, and 4% infant ALL. Patients with B-progenitor cell ALL were stratified by age and leukocyte count and randomized to receive induction therapy comprised of vincristine, prednisone, and asparaginase with triple intrathecal chemotherapy (methotrexate, hydrocortisone, cytarabine), followed by intensification with moderate-dose MTX (Regimen A), moderate-dose MTX plus asparaginase (Regimen B), moderate-dose MTX plus cytarabine given early (Regimen C), or moderate-dose MTX plus cytarabine given over the first 16 months of therapy (Regimen D). Continuation therapy comprised mercaptopurine and methotrexate with vincristine plus prednisone pulses. Central nervous system preventive treatment was continued for two years. Patients with T-cell or B-cell ALL or infants less than 1 yr old were treated on individual very intensive multiagent therapy protocols. The 4-year event-free survival for all patients was 66.4% +/- 2.4%; B-precursor ALL approximately 72%, T-ALL approximately 50%, B-ALL approximately 60%, and infants less than 1 yr old approximately 16.5%. We conclude that about two-thirds of newly diagnosed children with ALL can be cured with this approach which spares the majority of children exposure to alkylating agents, anthracyclines, epipodophylotoxins, and irradiation, diminishing the risks of serious acute and late effects.

  View details for Web of Science ID A1992HX75100043

• T(2-14)(P13-Q32) - A RECURRING ABNORMALITY IN LYMPHOCYTIC-LEUKEMIA - A PEDIATRIC-ONCOLOGY-GROUP STUDY CANCER GENETICS AND CYTOGENETICS Watson, M. S., Land, V. J., Carroll, A. J., Pullen, J., Borowitz, M. J., Link, M. P., Amylon, M., Behm, F. G. 1992; 58 (2): 121-124

  Abstract

  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.

  View details for Web of Science ID A1992HK76700002

  View details for PubMedID 1551073

• OSTEOSARCOMA - GOOD-NEWS DESPITE CRUDE TOOLS JOURNAL OF CLINICAL ONCOLOGY Simone, J. V., Meyer, W. H., Link, M. P. 1992; 10 (1): 1-2

  View details for Web of Science ID A1992GW59200001

  View details for PubMedID 1727911

• ACUTE LYMPHOBLASTIC-LEUKEMIA OCCURRING AS A 2ND MALIGNANT NEOPLASM IN CHILDHOOD - REPORT OF 3 CASES AND REVIEW OF THE LITERATURE JOURNAL OF CLINICAL ONCOLOGY Hunger, S. P., Sklar, J., Link, M. P. 1992; 10 (1): 156-163

  Abstract

  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.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.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.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.

  View details for Web of Science ID A1992GW59200023

  View details for PubMedID 1309379

• ADJUVANT CHEMOTHERAPY OF HIGH-GRADE OSTEOSARCOMA OF THE EXTREMITY - UPDATED RESULTS OF THE MULTIINSTITUTIONAL OSTEOSARCOMA STUDY CLINICAL ORTHOPAEDICS AND RELATED RESEARCH Link, M. P., Goorin, A. M., Horowitz, M., Meyer, W. H., Belasco, J., Baker, A., Ayala, A., Shuster, J. 1991: 8-14

  Abstract

  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.

  View details for Web of Science ID A1991GF15100003

  View details for PubMedID 1884563

• NITROGEN-MUSTARD, VINCRISTINE, PROCARBAZINE, AND PREDNISONE AS ADJUVANT CHEMOTHERAPY IN THE TREATMENT OF MEDULLOBLASTOMA - A PEDIATRIC ONCOLOGY GROUP-STUDY JOURNAL OF NEUROSURGERY Krischer, J. P., Ragab, A. H., Kun, L., Kim, T. H., Laurent, J. P., Boyett, J. M., Cornell, C. J., Link, M., Luthy, A. R., Camitta, B. 1991; 74 (6): 905-909

  Abstract

  In a randomized postoperative trial, adjuvant post-irradiation chemotherapy, consisting of nitrogen mustard, vincristine, procarbazine, and prednisone (MOPP), was tested versus radiation therapy alone for newly diagnosed medulloblastoma in patients between 1 and 21 years of age. Patients treated with irradiation plus MOPP had a statistically significant increase in overall survival rate at 5 years posttreatment compared to patients treated with radiation therapy alone (74% vs. 56%; p = 0.06, adjusted for race and gender). Although the overall study failed to show a statistically significant advantage for irradiation plus MOPP in event-free survival (p = 0.18), statistical significance was attained in children 5 years of age or older (p = 0.05). More severe hematological toxicities occurred in the group with irradiation plus MOPP; however, this hematotoxicity appeared to be tolerable and acceptable. These results suggest that patients may benefit from combined irradiation and chemotherapy following surgery for medulloblastoma.

  View details for Web of Science ID A1991FN17600008

  View details for PubMedID 2033450

• HODGKINS-DISEASE - TREATMENT OF THE YOUNG-CHILD PEDIATRIC CLINICS OF NORTH AMERICA Donaldson, S. S., Link, M. P. 1991; 38 (2): 457-473

  Abstract

  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."

  View details for Web of Science ID A1991GC73400014

  View details for PubMedID 1747155

• CHANGING PATTERN OF PULMONARY METASTASES WITH ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OSTEOSARCOMA - RESULTS FROM THE MULTIINSTITUTIONAL OSTEOSARCOMA STUDY JOURNAL OF CLINICAL ONCOLOGY Goorin, A. M., Shuster, J. J., Baker, A., Horowitz, M. E., Meyer, W. H., Link, M. P. 1991; 9 (4): 600-605

  Abstract

  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).

  View details for Web of Science ID A1991FD86300009

  View details for PubMedID 2066757

• PHILADELPHIA-CHROMOSOME AND MONOSOMY-7 IN CHILDHOOD ACUTE LYMPHOBLASTIC-LEUKEMIA - A PEDIATRIC ONCOLOGY GROUP-STUDY BLOOD Russo, C., Carroll, A., Kohler, S., Borowitz, M., Amylon, M., Homans, A., Kedar, A., Shuster, J., Land, V., Crist, W., Pullen, J., Link, M. 1991; 77 (5): 1050-1056

  Abstract

  During an 8-year period, 3,638 children from institutions of the Pediatric Oncology Group (POG) were diagnosed with acute lymphoblastic leukemia (ALL). Fifty-seven patients had Philadelphia chromosome-positive (Ph1) ALL. Blast cells obtained at diagnosis from 13 of these 57 cases (23%) were also found to have partial or complete monosomy 7 (-7). This subgroup of children with Ph1/-7 ALL was comprised primarily of older males with early B-lineage ALL. Bone marrow specimens from six Ph1/-7 patients were studied further using the polymerase chain reaction and primers that flank the ALL, and chronic myelogenous leukemia breakpoints to determine the molecular characteristic of the 9;22 translocation. Rearrangements were detected in RNA from bone marrow and/or peripheral blood cells of six patients, although four were in hematologic remission at the time of the analysis. Five cases showed the ALL breakpoint, while one child with Ph1/-7 showed the chronic myelogenous leukemia breakpoint. The induction failure rate was much higher in this subgroup (31%) as compared with Ph1-negative cases, and the projected duration of event-free survival reflected the aggressive nature of this subgroup because no children are projected to remain in remission at 2 years. ALL with both the 9;22 translocation and -7 appears to represent a unique and previously undescribed subgroup of childhood ALL associated with a particularly adverse outcome. Leukemic transformation in such patients may involve the interaction of a dominant oncogene (Ph1) and a tumor suppressor gene (-7).

  View details for Web of Science ID A1991EZ33000019

  View details for PubMedID 1995090

• THE T(1-19)(Q23-P13) RESULTS IN CONSISTENT FUSION OF E2A AND PBX1 CODING SEQUENCES IN ACUTE LYMPHOBLASTIC LEUKEMIAS BLOOD Hunger, S. P., Galili, N., Carroll, A. J., Crist, W. M., Link, M. P., Cleary, M. L. 1991; 77 (4): 687-693

  Abstract

  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.

  View details for Web of Science ID A1991EX92200002

  View details for PubMedID 1671560

• LACK OF TRANSMISSION OF THE LIVE ATTENUATED VARICELLA VACCINE VIRUS TO IMMUNOCOMPROMISED CHILDREN AFTER IMMUNIZATION OF THEIR SIBLINGS PEDIATRICS Diaz, P. S., Au, D., Smith, S., Amylon, M., Link, M., Smith, S., Arvin, A. M. 1991; 87 (2): 166-170

  Abstract

  The safety of administering the live attenuated Oka/Merck varicella vaccine to the well siblings of children with malignancy was evaluated as a strategy for reducing the risk of household exposure to varicella among immunocompromised children. Susceptible well children were eligible for vaccination if the child with malignancy had leukemia, lymphoma, or solid tumor in remission for 3 months or longer. No evidence of vaccine virus transmission was found among 30 children with malignancy whose 37 healthy susceptible siblings were immunized with varicella vaccine. Varicella-zoster virus was not isolated from the oropharyngeal secretions taken from 17 vaccinees or their 14 immunocompromised siblings. None of the 30 immunocompromised children had vaccine-related rashes or showed immunologic evidence of subclinical varicella-zoster virus infection based on testing for varicella-zoster virus IgG antibodies and T-lymphocyte proliferation to varicella-zoster virus. Four healthy vaccinees eventually had mild breakthrough cases of varicella, with transmission to the high-risk sibling in 3 cases. However, even in these families, the immunocompromised children had been protected from household exposure varicella for at least 20 months early in the course of their immunosuppressive treatment.

  View details for Web of Science ID A1991EW34200008

  View details for PubMedID 1846236

• CONSISTENT INVOLVEMENT OF THE BCR GENE BY 9-22 BREAKPOINTS IN PEDIATRIC ACUTE LEUKEMIAS BLOOD Suryanarayan, K., Hunger, S. P., Kohler, S., Carroll, A. J., Crist, W., Link, M. P., Cleary, M. L. 1991; 77 (2): 324-330

  Abstract

  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.

  View details for Web of Science ID A1991ER71900015

  View details for PubMedID 1985699

• DOWN-REGULATED C-MYB EXPRESSION INHIBITS DNA-SYNTHESIS OF T-LEUKEMIA CELLS IN MOST PATIENTS CANCER RESEARCH Venturelli, D., MARIANO, M. T., Szczylik, C., Valtieri, M., Lange, B., Crist, W., Link, M., Calabretta, B. 1990; 50 (22): 7371-7375

  Abstract

  We have investigated the functional relevance of c-myb expression for DNA synthesis in patients' T-leukemia cells. [3H]Thymidine incorporation assays of 32 patients' leukemia cells exposed in vitro to c-myb sense or antisense oligodeoxynucleotides served to define two groups of patients: a responder group whose leukemia cells showed 2- to 16-fold lower levels of [3H]thymidine incorporation in c-myb antisense-treated cultures than in c-myb sense-treated cultures (20 patients) and a nonresponder group whose cells showed comparable [3H]thymidine incorporation levels in either c-myb sense- or antisense-treated cultures (12 patients). Down-regulation of c-myb mRNA levels in cells exposed to c-myb antisense oligodeoxynucleotides was comparable in both groups of patients, indicating that differential sensitivity to c-myb antisense oligodeoxynucleotides was not due to differential uptake of these oligodeoxynucleotides. DNA polymerase alpha mRNA levels were down-regulated in cells from the responders but were unaffected in the nonresponder group. These results suggest that c-myb is required for DNA synthesis in cells of many but not all T-leukemia patients and that leukemia cells in which DNA synthesis is not inhibited despite down-regulation of c-myb expression may have undergone some genetic change(s) that obviate(s) the requirement for myb protein.

  View details for Web of Science ID A1990EH00600045

  View details for PubMedID 2224864

• THE T(1-14)(P34-Q11) IS NONRANDOM AND RESTRICTED TO T-CELL ACUTE LYMPHOBLASTIC-LEUKEMIA - A PEDIATRIC ONCOLOGY GROUP-STUDY BLOOD Carroll, A. J., Crist, W. M., Link, M. P., Amylon, M. D., Pullen, D. J., Ragab, A. H., Buchanan, G. R., Wimmer, R. S., Vietti, T. J. 1990; 76 (6): 1220-1224

  Abstract

  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.

  View details for Web of Science ID A1990DZ19200022

  View details for PubMedID 2400810

• PHILADELPHIA-CHROMOSOME POSITIVE CHILDHOOD ACUTE LYMPHOBLASTIC-LEUKEMIA - CLINICAL AND CYTOGENETIC CHARACTERISTICS AND TREATMENT OUTCOME - A PEDIATRIC-ONCOLOGY-GROUP STUDY BLOOD Crist, W., Carroll, A., Shuster, J., Jackson, J., Head, D., Borowitz, M., Behm, F., Link, M., Steuber, P., Ragab, A., Hirt, A., Brock, B., Land, V., Pullen, J. 1990; 76 (3): 489-494

  Abstract

  Among 3,638 children with acute lymphoblastic leukemia (ALL) entered on Pediatric Oncology Group (POG) protocols between June 1981 and April 1989, successful cytogenetic studies were available for 2,519, 58 (2.3%) of which had the Philadelphia (Ph) chromosome detected. Features associated with the presence of the Ph chromosome were high leukocyte count (median, 33 x 10(9)/L), older age median, 9.6 years), a higher proportion of French-American-British L2 morphology, and a lower frequency of mediastinal mass. Immunologic marker studies at diagnosis in 56 Ph+ cases identified early pre-B ALL in 42 cases (75%), pre-B-cell in 9 (16%), and T-cell in 5 (9%). This distribution is similar to that found in Ph+ ALL. Intensive multiagent chemotherapy induced complete remissions in only 78% of eligible Ph+ patients compared with 96% of those without an identified Ph chromosome (P less than .001). Of 44 eligible Ph+ patients treated on POG frontline protocols for children with non-T, non-B-cell ALL, 27 have failed therapy, compared with 520 of 1,892 without an identified Ph chromosome (logrank P less than .001). Ph+ ALL is an aggressive form of acute leukemia that frequently presents in older children with a high leukocyte count, FAB L2 morphology, and a pseudodiploid karyotype, and becomes multidrug-resistant early. Thus, Ph+ cases require early identification to permit treatment with intensive induction regimens and experimental approaches such as bone marrow transplantation.

  View details for Web of Science ID A1990DR56700008

  View details for PubMedID 2378982

• NEAR-TRIPLOID AND NEAR-TETRAPLOID ACUTE LYMPHOBLASTIC-LEUKEMIA OF CHILDHOOD BLOOD Pui, C. H., Carroll, A. J., Head, D., Raimondi, S. C., Shuster, J. J., Crist, W. M., Link, M. P., Borowitz, M. J., Behm, F. G., Land, V. J., Nash, M. B., Pullen, D. J., Look, A. T. 1990; 76 (3): 590-596

  Abstract

  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.

  View details for Web of Science ID A1990DR56700022

  View details for PubMedID 2378987

• STAGE-I-II PEDIATRIC HODGKINS-DISEASE - LONG-TERM FOLLOW-UP DEMONSTRATES EQUIVALENT SURVIVAL RATES FOLLOWING DIFFERENT MANAGEMENT SCHEMES JOURNAL OF CLINICAL ONCOLOGY Donaldson, S. S., Whitaker, S. J., Plowman, P. N., Link, M. P., Malpas, J. S. 1990; 8 (7): 1128-1137

  Abstract

  The results of treatment of 171 children with stage I-II Hodgkin's disease from two institutions with differing approaches to management have been analyzed. At the Stanford University Medical Center/Children's Hospital at Stanford (SUMC/CHaS), pathologic staging followed by extended-field radiation alone or involved-field radiation plus combination chemotherapy have been cardinal to the management policy. At St Bartholomew's Hospital/The Hospital for Sick Children at Great Ormond Street (Barts/GOS), clinical staging only has been used over the last 10 years, and involved/regional-field radiotherapy used as the treatment of choice rather than extended-field radiotherapy. Some children at each institution received combined modality therapy as primary management. Relapse among children with stage I disease was a more frequent occurrence in the Barts/GOS series than in the SUMC/CHaS group. However, the survival rates from the two centers are identical, 91% at 10 years. The following scientific-philosophic question is asked: Should one maximally stage and treat all children to increase the likelihood of a high freedom from relapse (FFR; cure) rate, or is it acceptable to minimize the initial staging and treatment, realizing that a proportion of patients will fail and require salvage/rescue therapy? With the awareness of morbidity from pathologic staging and aggressive treatment, and the favorable survival data reported from specialized centers using differing approaches, treatment strategies should be directed toward the long-term goal of cure of disease with maximal quality of life. A multidisciplinary management philosophy undertaken at a center with extensive experience in pediatric Hodgkin's disease is important to achieving this goal.

  View details for Web of Science ID A1990DM20000003

  View details for PubMedID 2193117

• RESULTS OF TREATMENT OF CHILDHOOD LOCALIZED NON-HODGKINS-LYMPHOMA WITH COMBINATION CHEMOTHERAPY WITH OR WITHOUT RADIOTHERAPY NEW ENGLAND JOURNAL OF MEDICINE Link, M. P., Donaldson, S. S., Berard, C. W., Shuster, J. J., Murphy, S. B. 1990; 322 (17): 1169-1174

  Abstract

  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.

  View details for Web of Science ID A1990DA35100001

  View details for PubMedID 2183052

• Intensive sequential chemotherapy for children with acute myelogenous leukemia. Haematology and blood transfusion Grier, H. E., Gelber, R. D., Clavell, L. A., Camitta, B. M., Link, M. P., Garcea, M. J., Weinstein, H. J. 1990; 33: 193-197

  View details for PubMedID 2182411

• SMALL CELL OSTEO-SARCOMA - A CLINICOPATHOLOGIC STUDY OF 27 CASES CANCER AYALA, A. G., Ro, J. Y., Raymond, A. K., Jaffe, N., Chawla, S., Carrasco, H., Link, M., Jimenez, J., EDEIKEN, J., Wallace, S., Murray, J. A., Benjamin, R. 1989; 64 (10): 2162-2173

  Abstract

  We report a study of 27 patients with small cell osteosarcoma (SCO), 17 from the M. D. Anderson Cancer Center (MDAH) and ten from the Pediatric Oncology Group (POG). There were 12 male patients and 15 female patients; 19 were white, five were black, and three were Hispanic. They ranged from 6 to 28 years of age with a median of 14 years. Histologically there were three patterns: Ewing's-like, lymphoma-like, and spindle cell. All cases showed osteoid formation and a few had chondroid areas. There was cytoplasmic glycogen in ten cases. Initial treatment for MDAH patients included intraarterial infusion of cisplatin in ten, amputation in four, partial mandibulectomies in two, and biopsy with local radiotherapy and systemic chemotherapy in one. All POG patients had resection or amputation followed by adjuvant chemotherapy. Twelve patients are alive, of whom nine have had significant follow-ups for 25 to 90 months. Fourteen patients are dead of lung, spine, and brain metastases from 1 to 23 months after initial diagnosis. One patient is alive with lung relapse at 4 months. In summary, SCO is a high-grade variant of osteosarcoma, with an incidence of up to 4% of all osteosarcomas, that affects patients of the same age group and has the same anatomic location as conventional osteosarcoma. Currently, SCO appears to have a prognosis that is the same as or slightly worse than that of conventional osteosarcoma. Furthermore, although intraarterial infusion is effective for the primary tumors in the bone, distant metastases are difficult to control.

  View details for Web of Science ID A1989AX22000030

  View details for PubMedID 2804905

• AGGRESSIVE MANAGEMENT OF 2ND PRIMARY TUMORS IN SURVIVORS OF HEREDITARY RETINOBLASTOMA INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Smith, L. M., Donaldson, S. S., Egbert, P. R., Link, M. P., Bagshaw, M. A. 1989; 17 (3): 499-505

  Abstract

  Survivors of hereditary retinoblastoma are at increased risk for the development of second primary tumors, most commonly osteosarcoma. Recent molecular genetic data demonstrate that a pleiotrophic effect of the retinoblastoma gene may be responsible for the development of these sarcomas. This report describes the incidence of second nonocular malignancies among 53 infants seen at Stanford University Medical Center who have been followed a median of 11.7 years. Of these, 42 initially had bilateral disease and eleven had unilateral disease. Of 53 infants, 50 received irradiation either as part of the initial therapy or as treatment for recurrent disease. The actuarial survival for the entire group is 67% at 30 year follow-up with a median survival of 79% at 11.7 years. Eight patients developed eleven second primary tumors. All occurred in the group having hereditary retinoblastoma. Eight were within the previously irradiated field and three were at distant sites. The second tumors included seven osteosarcomas, one angiosarcoma, one rhabdomyosarcoma, one malignant fibrous histiocytoma, and one unclassifiable round blue cell tumor. The actuarial incidence of the development of a second primary malignancy was 6% at 10 years, 19% at 20 years, and 38% at 30 years. The latent period from treatment of retinoblastoma to the diagnosis of malignancy ranged from 5.2 years to 36.2 years (median 16 years). An aggressive approach with combined modality therapy including radical resection, re-irradiation and/or chemotherapy was used to treat these second primary tumors in five of eight patients. In four of the five, there was no evidence of disease at 22-72 months following treatment. In the three patients who did not receive aggressive combined treatment, there were no survivors. These data confirm the previously reported risk of developing a second primary tumor among survivors with hereditary retinoblastoma. Careful long-term follow-up for this genetically susceptible group is essential for early detection and implementation of curative therapy.

  View details for Web of Science ID A1989AP69000007

  View details for PubMedID 2777644

• ABSENCE OF IG-V REGION GENE SOMATIC HYPERMUTATION IN ADVANCED BURKITTS-LYMPHOMA JOURNAL OF IMMUNOLOGY Carroll, W. L., Yu, M., Link, M. P., Korsmeyer, S. J. 1989; 143 (2): 692-698

  Abstract

  Somatic hypermutation of rearranged Ig V region gene plays a major role in generating antibody diversity. Recently, V mutation has been established as a major mechanism of tumor escape from anti-Id immunotherapy. We cloned and sequenced the expressed Ig H and L chain V regions from a case of B acute lymphoblastic leukemia in order to evaluate B cell stages associated with V region mutation, and to determine which tumors would be better suited to Id directed immunotherapy. A consensus VH and V lambda sequence representing tumor at diagnosis was obtained by conventional cDNA cloning in lambda gt10 from a heterohybridoma. Primers which flanked both V regions were used in a modified polymerase chain reaction to generate multiple independent sequences from tumor cells harvested at relapse. In order to exclude mutations due to infidelity of the amplification procedure, single cDNA templates of known sequence were also amplified. The polymerase chain reaction proved to be an effective procedure to obtain multiple clones, but replication in M13 was associated with a low rate of base misincorporation. The results indicate that there is no evidence for biologically significant ongoing mutation in this t(8;14) B cell tumor when comparing sequences at diagnosis and relapse. Thus, V somatic mutation may be restricted to a discrete B cell stage whose malignant counterpart is follicular lymphoma.

  View details for Web of Science ID A1989AE59700046

  View details for PubMedID 2500485

• DIFFUSE SMALL NONCLEAVED CELL LYMPHOMA IN CHILDREN, BURKITT VERSUS NON-BURKITT TYPES - RESULTS FROM THE PEDIATRIC ONCOLOGY GROUP AND ST-JUDE-CHILDRENS-RESEARCH-HOSPITAL CANCER Hutchison, R. E., Murphy, S. B., Fairclough, D. L., Shuster, J. J., Sullivan, M. P., Link, M. P., Donaldson, S. S., Berard, C. W. 1989; 64 (1): 23-27

  Abstract

  The clinical relevance of a morphologic distinction between Burkitt's (B) and non-Burkitt's (NB) types of small non-cleaved cell (SNC) non-Hodgkin's lymphoma (NHL) has been controversial. Numerous attempts to discern an important clinical difference between the subtypes have failed to provide a convincing reason to maintain this distinction for other than descriptive purposes. Because of conflicting reports in the literature, the authors have analyzed 183 cases of SNC NHL in children from the Pediatric Oncology Group and 129 from St. Jude Children's Research Hospital (Memphis, TN). The results from both series, which consist of approximately the same proportions of B and NB subtypes, (i.e., approximately 54%-58% B, 36% NB, and 6%-10% not otherwise specified) show no significant differences in age at presentation, extent of disease, primary site of involvement, or survival. The authors conclude that the morphologic distinction between B and NB types of SNC NHL in children lacks demonstrable clinical importance.

  View details for Web of Science ID A1989AB56100004

  View details for PubMedID 2731117

• LONG-TERM GROWTH OF MALIGNANT THYMOCYTES INVITRO BLOOD Smith, S. D., McFall, P., Morgan, R., Link, M., Hecht, F., Cleary, M., Sklar, J. 1989; 73 (8): 2182-2187

  Abstract

  We report a new methodology for the long-term growth of malignant T-lymphoblasts from patients with T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LL). When malignant cells were cultured in the presence of insulin-like growth factor I under hypoxic conditions, cellular proliferation occurred that resulted in the establishment of immortal cell lines from ten of 12 patient tumors. Authenticity of each cell line was verified by a direct comparison of the immunophenotype, karyotype, and immunogenotype with the patient's tumor cells. This improved method of cell culture permits frequent establishment of cell lines from patients with T-ALL/T-LL, thereby aiding in analysis of thymocyte transformation and neoplasia.

  View details for Web of Science ID A1989U940100020

  View details for PubMedID 2786436

• CYTO-TOXIC LYMPHOCYTE-T SPECIFIC FOR SELF TUMOR IMMUNOGLOBULIN EXPRESS T-CELL RECEPTOR DELTA-CHAIN JOURNAL OF EXPERIMENTAL MEDICINE Wright, A., Lee, J. E., Link, M. P., Smith, S. D., Carroll, W., Levy, R., CLAYBERGER, C., KRENSKY, A. M. 1989; 169 (5): 1557-1564

  Abstract

  CTL are thought to play a role in the elimination of transformed cells in vivo. The effectiveness of such CTL is in part dependent on recognition of tumor specific antigens. Among the best characterized tumor-specific antigens are the unique or idiotypic determinants on the Ig of B cell lymphomas. Here we describe the generation and properties of human CTL specific for the idiotype on autologous B cell tumors. These cells are CD3+,CD4-,CD8- and express the delta chain of the TCR. Such cells may prove useful in tumor-specific adoptive therapy.

  View details for Web of Science ID A1989U366600004

  View details for PubMedID 2541219

• PEDIATRIC HODGKINS-DISEASE - PULMONARY, CARDIAC, AND THYROID-FUNCTION FOLLOWING COMBINED MODALITY THERAPY INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS MEFFERD, J. M., Donaldson, S. S., Link, M. P. 1989; 16 (3): 679-685

  Abstract

  Since pediatric Hodgkin's disease is a curable malignancy, it is essential to limit treatment sequelae. This study examines post-treatment pulmonary, cardiac, and thyroid function in 34 children, ages 5 to 17 (23 male and 11 female) with Hodgkin's disease. All received combined modality therapy of 6 cycles of alternating ABVD/MOPP chemotherapy and low dose (1500-2500 cGy) involved field radiotherapy. Mean follow-up period is 27.5 months with actuarial freedom from relapse of 94% and survival of 92%. Twenty asymptomatic patients underwent pulmonary function testing following chemotherapy and supradiaphragmatic radiotherapy. Eleven patients had post-treatment carbon monoxide diffusing capacity (DLCO) performed. Six of 11 children (55%) had abnormal values (mean 66%, range 58-80) showing either a reduced DLCO compared to pretreatment or an low absolute value. Eight of the twenty patients (40%) tested post-treatment for FEV1, FVC, TLC and flow volume loop had abnormal results. Six showed restrictive abnormalities and two had obstructive dysfunction. Fourteen patients underwent cardiac nuclear gated angiogram after completion of chemotherapy. Two asymptomatic patients (14%) had abnormal scans showing either a low resting ejection fraction or a decreased response to exercise. Thyroid function was evaluated post-treatment in twenty-one patients by TSH, T4, free T4 or sensitive TSH analysis. Four (21%) had an elevated TSH with a normal T4 after treatment. Although post-treatment thyroid and cardiac effects were minimal, post-treatment pulmonary dysfunction in asymptomatic patients was substantial with more than 50% of tested children demonstrating an abnormal DLCO and 40% showing restrictive or obstructive pulmonary parameters. These abnormalities were observed following a maximum bleomycin dose of 60 units/m2. Bleomycin and pulmonary radiotherapy have adverse effects on diffusing capacity and the long-term pulmonary sequlae of combined ABVD chemotherapy and radiotherapy are unknown. Our analysis suggests that even in asymptomatic children, pulmonary abnormalities are frequent.

  View details for Web of Science ID A1989T723100019

  View details for PubMedID 2466027

• CEREBELLAR ATROPHY CAUSED BY HIGH-DOSE CYTOSINE-ARABINOSIDE - CT AND MR FINDINGS AMERICAN JOURNAL OF ROENTGENOLOGY Miller, L., Link, M. P., Bologna, S., Parker, B. R. 1989; 152 (2): 343-344

  View details for Web of Science ID A1989R891600024

  View details for PubMedID 2783512

• Clinical investigations of children with Hodgkin's disease at Stanford University Medical Center. A preliminary overview using low-dose irradiation and alternating ABVD/MOPP chemotherapy. Cancer treatment and research Donaldson, S. S., Link, M. P., McDougall, I. R., Parker, B. R., Shochat, S. J. 1989; 41: 307-315

  View details for PubMedID 2484294

• POOR-RISK NON-LYMPHOBLASTIC LYMPHOMA OF CHILDHOOD - RESULTS OF AN INTENSIVE PILOT-STUDY MEDICAL AND PEDIATRIC ONCOLOGY Finlay, J. L., Trigg, M. E., Link, M. P., Frierdich, S. 1989; 17 (1): 29-38

  Abstract

  Children with "poor-risk" nonlymphoblastic lymphoma, especially those with marrow or nervous system (CNS) involvement at presentation, have fared poorly even on aggressive chemotherapy regimens. We report here the results of a pilot study of 30 children treated with a highly intensive chemotherapy regimen. This regimen includes an intensive Induction Phase consisting of three cycles of CHOP therapy (cyclophosphamide, doxorubicin, vincristine, and corticosteroids) as well as intensive intrathecal therapy with each cycle. This is followed by a CNS Consolidation Phase consisting of a single cycle of CHOP therapy with five intrathecal doses of "triple" chemotherapy (methotrexate, cytosine arabinoside, and hydrocortisone). Thereafter, a Maintenance Phase consists of alternating cycles of 1) cytosine arabinoside and 6-thioguanine, 2) oral methotrexate and VP-16, and 3) CHOP, for a duration that varied from 36 to 72 wk. Neither debulking surgery nor radiation therapy were recommended. There were 20 patients with Stage III disease (St. Jude's Staging System) and an additional ten patients with bone marrow and/or CNS involvement. The latter group included six patients with B-cell leukemia, three of whom also had CNS disease at presentation. Two additional patients had CNS disease without marrow involvement. Twenty-nine of 30 patients achieved a complete response. Six patients died with recurrent or progressive disease. Twenty-three patients are alive without any adverse events between 21 and 65 mo after diagnosis, with the median time of survival not yet reached (at least 32 mo). All seven adverse events occurred within 7 mo of diagnosis. Event-free survival for all patients is 77%, for Stage III patients is 80%, and for patients with marrow and/or CNS involvement is 70%. This pilot study offers encouragement for improvement in the prognosis of children with "poor-risk" nonlymphoblastic lymphoma and merits evaluation in a Phase III randomized trial in the multicenter cooperative group setting.

  View details for Web of Science ID A1989R919400006

  View details for PubMedID 2913472

• CONTINUING REARRANGEMENT BUT ABSENCE OF SOMATIC HYPERMUTATION IN IMMUNOGLOBULIN GENES OF HUMAN B-CELL PRECURSOR LEUKEMIA JOURNAL OF EXPERIMENTAL MEDICINE Bird, J., Galili, N., Link, M., Stites, D., Sklar, J. 1988; 168 (1): 229-245

  Abstract

  Southern blot analyses revealed that cells from nearly 30% of childhood B cell precursor acute lymphoblastic leukemias (ALLs) contained more than two rearranged, nongermline bands for Ig heavy chain genes. DNA corresponding to these bands was molecularly cloned from two cases which showed three and seven rearranged bands, respectively. Nucleotide sequence analysis of the cloned DNA demonstrated that each band represented different VDJ or DJ rearrangements. While the same DJ joints were shared by several rearrangements, different DJ joints were found in the majority of rearrangements, precluding V region substitution as an explanation for the multiplicity of heavy chain rearrangements in these leukemias. Most of the V region segments involved in these rearrangements were restricted to VH region families that have been shown previously to be preferentially rearranged in human fetal B lineage cells. Sequence analysis of multiple copies of the same VDJ rearrangements from different cells revealed no somatic mutation, a mechanism responsible for detection of extra rearranged Ig DNA bands in certain other B lineage tumors. The data suggest that in some cases of ALL Ig heavy chain genes begin and continue to rearrange de novo within the neoplastic B cell precursor populations derived from an original malignant cell transformed at a stem cell stage of differentiation.

  View details for Web of Science ID A1988P474800018

  View details for PubMedID 2840480

• TREATMENT OF OSTEO-SARCOMA LANCET Link, M. P. 1988; 1 (8598): 1334-1334

  View details for Web of Science ID A1988N728900027

  View details for PubMedID 2897579

• PHILADELPHIA CHROMOSOME-POSITIVE ACUTE LYMPHOBLASTIC-LEUKEMIA CELL-LINES WITHOUT CLASSICAL BREAKPOINT CLUSTER REGION REARRANGEMENT CANCER RESEARCH Naumovski, L., Morgan, R., Hecht, F., Link, M. P., Glader, B. E., Smith, S. D. 1988; 48 (10): 2876-2879

  Abstract

  The Philadelphia (Ph) chromosome translocation which is classically observed in chronic myeloid leukemia (CML) is sporadically found in acute lymphoblastic leukemia (ALL). In CML the translocation breakpoint on chromosome 22 is within the breakpoint cluster region, while in childhood ALL, no detectable change in breakpoint cluster region is routinely observed. In order to investigate the nature of this difference, we have established and characterized two cell lines from a child with Ph positive ALL. The cell lines have retained the cytochemical staining pattern, enzyme activity, monoclonal antibody profile, and immunoglobulin gene rearrangements of the child's malignant cells. The cell lines had the same Ph translocation t(9;22) (q34;q11) as the child's malignant cells along with additional chromosome changes. Southern blot analysis showed that the Ph translocation did not involve the 5.8-kilobase breakpoint cluster region segment characteristically seen in CML. The cell lines reported here will be a valuable resource in ascertaining the biological significance of the Ph translocation seen in ALL.

  View details for Web of Science ID A1988N269700042

  View details for PubMedID 3162827

• IDIOTYPE AS A TUMOR-SPECIFIC MARKER IN CHILDHOOD B-CELL ACUTE LYMPHOBLASTIC-LEUKEMIA BLOOD Carroll, W. L., Link, M. P., Cleary, M. L., Bologna, S., CARSWELL, C., Amylon, M. D., Smith, S. D., Levy, R. 1988; 71 (4): 1068-1073

  Abstract

  Immunoglobulin (Ig) or idiotype (Id) is a tumor-specific target in those B cell malignancies that express this molecule on their surface. We explored the biology of B cell acute lymphoblastic leukemia (B cell ALL) using Id as a tumor marker. In this report we describe the development of anti-Id monoclonal antibodies (MAB) for two children with B cell ALL. These reagents were used retrospectively to study tumor kinetics and to detect residual disease after chemotherapy. In both cases serum Id values were strikingly high at diagnosis (1.2 mg/mL and 10.8 mg/mL), suggesting that the tumor cells were relatively mature B cells capable of significant antibody production. In both patients the serum Id levels fell with the institution of therapy and confirmed that the patients were in remission. Increasing serum Id predicted relapse four months before conventional methods in patient 1, and Id proved to be a more sensitive measure of tumor burden than Southern blot analysis of rearranged Ig genes in bone marrow samples. Surprisingly, low levels of Id were redetected in the second patient just before completing therapy and have persisted for over a year despite the absence of clinical evidence of recurrent disease. Thus, serum Id levels reflect tumor burden during initial therapy but may not necessarily predict tumor progression after a complete clinical remission.

  View details for Web of Science ID A1988M985300037

  View details for PubMedID 3128346

• CLINICAL AND BIOLOGIC CHARACTERIZATION OF T-CELL NEOPLASIAS WITH REARRANGEMENTS OF CHROMOSOME-7 BAND Q34 BLOOD Smith, S. D., Morgan, R., Gemmell, R., Amylon, M. D., Link, M. P., Linker, C., Hecht, B. K., Warnke, R., Glader, B. E., Hecht, F. 1988; 71 (2): 395-402

  Abstract

  In T cell malignancy, rearrangements of chromosome 14 have been observed with a break in the band that contains the alpha chain gene for the T cell receptor (TCR). Because the beta chain TCR gene is in chromosome band 7q34, we searched for and report finding specific rearrangements of 7q34 exclusively in T cell malignancies. The rearrangements were reciprocal translocations between 7q34 and other points: 1p34, 9q32, 9q34, 15q22, and 19p13. The malignancies containing a 7q34 translocation were either T cell acute lymphoblastic leukemias or T cell lymphoblastic lymphomas that had similarities in clinical, enzyme, immunologic, and cellular characteristics. Hybridization using a probe to the beta-TCR gene disclosed unique rearrangements consistent with clonality in every case. A common pattern with chromosome breakpoints involving TCR genes may be emerging in T cell neoplasia.

  View details for Web of Science ID A1988L922400019

  View details for PubMedID 2962650

• ABSENCE OF CELL-SURFACE LFA-1 AS A MECHANISM OF ESCAPE FROM IMMUNOSURVEILLANCE LANCET CLAYBERGER, C., Medeiros, L. J., Link, M. P., Warnke, R. A., Wright, A., KOLLER, T. D., Smith, S. D., KRENSKY, A. M. 1987; 2 (8558): 533-536

  Abstract

  During studies of T-cell recognition of autologous tumour cells, a number of tumour cell lines derived from patients with lymphoma proved to be poor stimulators of both autologous and allogeneic T-cell responses. Analysis of the tumour cell surface molecules indicated that expression of the lymphocyte-function-associated antigen, LFA-1, was lacking, whereas normal leucocytes from these patients expressed normal levels of LFA-1. Examination of other lymphoid tumours revealed that most high grade lymphomas, but not most low or intermediate grade lymphomas, do not express the LFA-1 molecule. Furthermore, in an initial survey, the tumours from 5 of 7 patients with non-relapsing large cell lymphomas expressed LFA-1 whereas only 3 of 18 patients with relapsing lymphomas had tumours that did so. These findings suggest that tumour cells lacking surface LFA-1 cannot initiate an effective immune response in vivo. This lack of immunogenicity might contribute to escape from immunosurveillance.

  View details for Web of Science ID A1987J846800004

  View details for PubMedID 2887833

• WEEKLY HIGH-DOSE METHOTREXATE AND DOXORUBICIN FOR OSTEOSARCOMA - THE DANA-FARBER-CANCER-INSTITUTE THE CHILDRENS-HOSPITAL - STUDY-III JOURNAL OF CLINICAL ONCOLOGY Goorin, A. M., PEREZATAYDE, A., Gebhardt, M., Andersen, J. W., Wilkinson, R. H., DELOREY, M. J., Watts, H., Link, M., Jaffe, N., Frei, E., Abelson, H. T. 1987; 5 (8): 1178-1184

  Abstract

  Weekly high-dose methotrexate with leucovorin rescue and vincristine (HDMTX) and doxorubicin was administered as adjuvant postoperative therapy to 46 patients with a diagnosis of conventional high-grade nonmetastatic osteosarcoma of an extremity between July 1976 and December 1981. The primary lesions were managed by wide or radical amputation (26 patients) or by limb-sparing resection in 20 selected patients. The margins of the resections were retrospectively classified as marginal in three, wide in 16, and radical in one. The 5-year relapse-free survival (RFS) for all patients is 59% (95% confidence interval [CI], 43%, 74%) and overall survival is 78% (95% CI, 65%, 91%). The RFS for patients initially having a limb resection procedure is 55% (95% CI, 32%, 77%) compared with 62% (95% CI, 43%, 81%) for those initially having amputations (P = .52). Using multivariate analysis, the only significant prognostic variables that predicted RFS of greater than or equal to 3 years, were the presence of moderate to marked lymphocytic infiltration of the primary tumor (P less than .002), primary site outside of the proximal humerus (P less than .005), and the absence of a predominance of osteoblastic pattern in the primary tumor (P less than .03).

  View details for Web of Science ID A1987J589500007

  View details for PubMedID 3476688

• PROGNOSTIC FACTORS IN CHILDHOOD ACUTE MYELOGENOUS LEUKEMIA JOURNAL OF CLINICAL ONCOLOGY Grier, H. E., Gelber, R. D., Camitta, B. M., DELOREY, M. J., Link, M. P., Price, K. N., Leavitt, P. R., Weinstein, H. J. 1987; 5 (7): 1026-1032

  Abstract

  The prognostic significance of initial clinical and laboratory parameters was evaluated in 125 children with acute myelogenous leukemia (AML) treated on two consecutive protocols (VAPA and 80-035). Both protocols used an anthracycline with cytosine arabinoside (ara-C) for induction therapy followed by 12 to 14 months of intensive sequential postremission chemotherapy. Results are similar for the two treatment regimens. Seventy-two percent of patients achieved a complete remission, with 42% projected 5-year disease-free survival for the complete responders. Monocytic or myelomonocytic leukemic subtype (French-American-British [FAB] types M4 and M5), WBC count less than 100,000/microL, and age less than 2 years at diagnosis all predicted increased risk of relapse and decreased overall survival in univariate analyses. FAB subtype and high white count continued to predict for an increased risk of relapse in multivariate analyses and only M5 leukemic subtype independently predicted for poor survival. Patients with M4 or M5 leukemic subtype had a higher incidence of initial relapses in the CNS. The addition of intrathecal cytosine arabinoside in the second protocol, 80-035, decreased the percentage of patients with initial failure in the CNS, but did not improve overall survival. Improved CNS prophylaxis, better systemic therapy, and/or different treatment strategies are needed to improve therapy in these high-risk patients.

  View details for Web of Science ID A1987J134800008

  View details for PubMedID 3474356

• GIANT-CELL PNEUMONIA CAUSED BY PARA-INFLUENZA TYPE-3 IN A PATIENT WITH ACUTE MYELOMONOCYTIC LEUKEMIA ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE Weintrub, P. S., Sullender, W. M., Lombard, C., Link, M. P., Arvin, A. 1987; 111 (6): 569-570

  Abstract

  A 4 1/2-year-old boy with acute myelomonocytic leukemia developed fever, neutropenia, and a prolonged respiratory illness while receiving maintenance chemotherapy. An open lung biopsy specimen demonstrated a giant cell pneumonia with intracytoplasmic and probable intranuclear viral inclusions of the paramyxovirus type. Serologic studies demonstrated convincing evidence of a parainfluenza type 3 infection. Although parainfluenza type 3-induced giant cell pneumonia has been reported in infants with the severe combined immunodeficiency syndrome, to our knowledge, this is the first reported case of this complication in a patient with leukemia.

  View details for Web of Science ID A1987H468400022

  View details for PubMedID 3034189

• COMBINED MODALITY TREATMENT WITH LOW-DOSE RADIATION AND MOPP CHEMOTHERAPY FOR CHILDREN WITH HODGKINS-DISEASE JOURNAL OF CLINICAL ONCOLOGY Donaldson, S. S., Link, M. P. 1987; 5 (5): 742-749

  Abstract

  High doses of radiation administered to children with Hodgkin's disease may be associated with long-term alterations in soft tissue and bone growth. In an attempt to minimize this complication, we initiated a protocol using low doses of radiation in conjunction with six cycles of MOPP (nitrogen mustard, vincristine, procarbazine, prednisone) chemotherapy in newly diagnosed, pathologically staged children with Hodgkin's disease. Of 55 children treated in this fashion, the actuarial survival and freedom from relapse rates are 89% and 90%, respectively, with median follow-up of 7 1/2 years and maximum follow-up of 15 1/2 years. The local control rate is 97%. The previously encountered growth alteration did not occur when lower doses of radiation were used. However, three children developed acute leukemia. This study demonstrates that the vast majority of children with Hodgkin's disease can be cured with combined modality therapy. This experience provides long-term follow-up and thus serves as the basis for new ongoing protocols using low-dose involved field radiation with new drug combinations.

  View details for Web of Science ID A1987H206400011

  View details for PubMedID 3572464

• IMPROVED RESULTS OF TREATMENT OF ADULT ACUTE LYMPHOBLASTIC-LEUKEMIA BLOOD Linker, C. A., Levitt, L. J., ODONNELL, M., Ries, C. A., Link, M. P., Forman, S. J., FARBSTEIN, M. J. 1987; 69 (4): 1242-1248

  Abstract

  We designed a treatment program to improve the outcome for adults with acute lymphoblastic leukemia (ALL). Treatment included a remission-induction phase followed by intensive alternating cycles of non-cross-resistant chemotherapy and prolonged oral maintenance therapy. Eighty-one consecutive previously untreated patients were entered on this study. Ninety-four percent of patients entered complete remission. A Kaplan-Meier analysis predicts that 53% +/- 9% (SEM) of patients in remission will remain free of disease at 3 years. Neither age, sex, WBC count, nor immunophenotype had a significant effect on remission duration. This program of intensive cyclical chemotherapy has improved the disease-free survival of patients with adult ALL.

  View details for Web of Science ID A1987G733000041

  View details for PubMedID 3470055

• QUANTITATION AND ESTIMATION OF LYMPHOCYTE SUBSETS IN TISSUE-SECTIONS - COMPARISON WITH FLOW-CYTOMETRY AMERICAN JOURNAL OF CLINICAL PATHOLOGY Garcia, C. F., Weiss, L. M., Lowder, J., KOMOROSKE, C., Link, M. P., Levy, R., Warnke, R. A. 1987; 87 (4): 470-477

  Abstract

  A quantitation method for lymphocyte subsets in immunoperoxidase-stained frozen tissue sections was compared with flow cytometry in 23 cases of non-Hodgkin's lymphoma. Close correlations were obtained, demonstrating the accuracy of the technic. Weak intensity of fluorescence and fragility of the tumor cells during the fluorescence-activated cell sorter (FACS) analyses were the most likely explanations for a number of the discrepancies observed. The tissue quantitation method was precise, particularly at low values, where it was better than the FACS. A simpler and faster estimation method employing categories within 10 percentage units was also tested in this study; this method correlated as well with the FACS as the quantitation method and gave the best interobserver correlations.

  View details for Web of Science ID A1987G546900006

  View details for PubMedID 3103419

• ESTABLISHMENT AND CHARACTERIZATION OF A COMMON ACUTE LYMPHOBLASTIC-LEUKEMIA CELL-LINE WITH A DELETION OF CHROMOSOME-3 BAND Q26 CANCER RESEARCH Smith, S. D., Morgan, R., Galili, N., Amylon, M. D., Link, M. P., Hecht, F., Sklar, J., Glader, B. E. 1987; 47 (6): 1652-1656

  Abstract

  This paper describes the establishment and characterization of a new cell line (SUP-B7) which was established from a child with "common" acute lymphoblastic leukemia. The SUP-B7 cells (and the patient's tumor) have been characterized by cytochemical staining, monoclonal antibodies, enzyme analyses, gene rearrangement studies, and karyotype analysis. The SUP-B7 cells are periodic acid-Schiff positive, common acute lymphoblastic leukemia antigen positive, and terminal deoxynucleotidyl transferase positive, and they lack the Epstein-Barr virus genome. In addition, the SUP-B7 cells lack cytoplasmic and surface immunoglobulins, and the immunoglobulin gene rearrangement studies showed rearranged heavy chain genes with germ line light chain genes. Concordance between the cell line and the patient's tumor was established by the immunoglobulin gene rearrangement studies. Using Southern blot analysis of the DNA from the patient's tumor and the SUP-B7 cells, there was comigration of the bands representing the rearranged immunoglobulin heavy chain gene. In addition, the SUP-B7 cells possess a single chromosome abnormality: del(3)(q26q28), with the chromosome breakpoint at or near the transferrin receptor gene. Since the SUP-B7 cell line is concordant with the patient's malignancy and since these cells possess a single chromosomal abnormality, the SUP-B7 cell line may be a useful tool in determining the biological significance of the chromosome deletion: del(3)(q26q28).

  View details for Web of Science ID A1987G548300030

  View details for PubMedID 3469019

• Postremission induction intensive sequential chemotherapy for children with AML--treatment results and prognostic factors. Haematology and blood transfusion Weinstein, H., Grier, H., Gelber, R., Camitta, B., Link, M., Delorey, M., Price, K. 1987; 30: 88-92

  View details for PubMedID 3476388

• A UNIQUE ANTIGEN ON MATURE B-CELLS DEFINED BY A MONOCLONAL-ANTIBODY JOURNAL OF IMMUNOLOGY Link, M. P., Bindl, J., MEEKER, T. C., CARSWELL, C., DOSS, C. A., Warnke, R. A., Levy, R. 1986; 137 (9): 3013-3018

  Abstract

  A novel 42,000 dalton antigen (MB-1) expressed by mature human B cells in blood and tonsil was identified and characterized by utilizing a hybridoma monoclonal antibody. A comparison of MB-1 with other known B cell antigens suggests that the MB-1 antigen has not been previously identified. From one-and two-color immunofluorescence studies, it appears that the MB-1 antigen is found on all normal immunoglobulin (Ig)-expressing cells, but not on T cells, thymocytes, granulocytes, or platelets. Studies of malignant B cell tumors reveal that the antigen is expressed by virtually all Ig-expressing B cell tumors but only 10% of SIg- B-lineage leukemias. Data from these studies suggest that the MB-1 antigen is expressed late in B cell ontogeny before the expression of SIg.

  View details for Web of Science ID A1986E489100045

  View details for PubMedID 3489782

• COMMON MECHANISM OF CHROMOSOME INVERSION IN B-CELL AND T-CELL TUMORS - RELEVANCE TO LYMPHOID DEVELOPMENT SCIENCE Denny, C. T., Hollis, G. F., Hecht, F., Morgan, R., Link, M. P., Smith, S. D., Kirsch, I. R. 1986; 234 (4773): 197-200

  Abstract

  An inversion of chromosome 14 present in the tumor cells of a patient with childhood acute lymphoblastic leukemia of B-cell lineage was shown to be the result of a site-specific recombination event between an immunoglobulin heavy-chain variable gene and the joining segment of a T-cell receptor alpha chain. This rearrangement resulted in the formation of a hybrid gene, part immunoglobulin and part T-cell receptor. Furthermore, this hybrid gene was transcribed into messenger RNA with a completely open reading frame. Thus, two loci felt to be normally activated at distinct and disparate points in lymphocyte development were unified and expressed in this tumor.

  View details for Web of Science ID A1986E225800030

  View details for PubMedID 3092355

• CHROMOSOME-9 ABNORMALITIES IN CHILDHOOD T-CELL LEUKEMIA NEW ENGLAND JOURNAL OF MEDICINE Smith, S. D., Link, M. P., Trela, M., Amylon, M., Sklar, J., Morgan, R., Hecht, F. 1986; 315 (3): 195-196

  View details for Web of Science ID A1986D192800023

  View details for PubMedID 3487732

• THE EFFECT OF ADJUVANT CHEMOTHERAPY ON RELAPSE-FREE SURVIVAL IN PATIENTS WITH OSTEOSARCOMA OF THE EXTREMITY NEW ENGLAND JOURNAL OF MEDICINE Link, M. P., Goorin, A. M., Miser, A. W., Green, A. A., Pratt, C. B., Belasco, J. B., Pritchard, J., Malpas, J. S., BAKER, A. R., Kirkpatrick, J. A., AYALA, A. G., Shuster, J. J., Abelson, H. T., Simone, J. V., Vietti, T. J. 1986; 314 (25): 1600-1606

  Abstract

  We conducted a randomized controlled trial to determine whether intensive multi-agent adjuvant chemotherapy improves the chances of relapse-free survival in patients with nonmetastatic high-grade osteosarcoma of the extremity, as compared with concurrent controls. After undergoing definitive surgery, 36 patients were randomly assigned to adjuvant chemotherapy or to observation without adjuvant treatment. At two years the actuarial relapse-free survival was 17 percent in the control group, similar to that found in studies before 1970, and 66 percent in the adjuvant-chemotherapy group (P less than 0.001). Similar results were observed among 77 additional patients who declined to undergo randomization but who elected observation or chemotherapy. We conclude that the natural history of osteosarcoma of the extremity has remained stable over the past two decades, that adjuvant chemotherapy increases the chances of relapse-free survival of patients with high-grade osteosarcoma, and that it should be given to all such patients.

  View details for Web of Science ID A1986C766900002

  View details for PubMedID 3520317

• CHRONIC INFECTIOUS-MONONUCLEOSIS SYNDROME, PANCYTOPENIA, AND POLYCLONAL B-LYMPHOPROLIFERATION TERMINATING IN ACUTE LYMPHOBLASTIC-LEUKEMIA AMERICAN JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY Finlay, J., Luft, B., Yousem, S., Wood, G. S., Link, M., Arvin, A., Glader, B., Lennette, E., Shatsky, M., Olds, L., BORCHERDING, W., Hong, R., PURTILO, D. 1986; 8 (1): 18-27

  Abstract

  A 17-year-old previously healthy girl is reported who developed acute infectious mononucleosis followed by progressive ill health over 20 months, associated with pancytopenia and a polyclonal B-lymphoproliferation, terminating in acute lymphoblastic leukemia (ALL). Epstein-Barr virus (EBV) was recovered from the patient's nasopharyngeal secretions; serologic titers of antibodies to EBV-associated antigens were compatible with a chronic persistent EBV infection. Plasma interferon levels were markedly elevated. EBV-specific cell-mediated immunity, as well as Natural killer (NK) cell activity were markedly deficient. Other studies of cell-mediated immunity revealed notable abnormalities, including abnormalities in T-cell subset ratios, and a serum blocker of autologous mitogen-induced lymphoproliferation. Humoral (plasma)-mediated, but not cell-mediated, suppression of hemopoiesis was demonstrated using in vitro erythroid and myeloid colony culture techniques. Immunophenotyping of the patient's bone marrow cells preterminally was consistent with ALL. Autopsy revealed pathologic changes of ALL in marrow and multiple organs. We conclude that our patient developed an EBV-driven lymphoproliferative disorder, with associated defective cell-mediated immunity and hemopoiesis. Ultimately, the patient's documented polyclonal lymphoproliferative state was superimposed by acute lymphoblastic leukemia.

  View details for Web of Science ID A1986C028900004

  View details for PubMedID 3013037

• CHROMOSOME CLUES TO ACUTE-LEUKEMIA IN DOWNS-SYNDROME CANCER GENETICS AND CYTOGENETICS Hecht, F., Hecht, B. K., Morgan, R., SANDBERG, A. A., Link, M. P. 1986; 21 (2): 93-98

  Abstract

  Surprisingly few cases of Down's syndrome with acute leukemia have been documented by chromosome banding studies of the leukemia cells. We studied a Down's syndrome child with acute myelomonocytic leukemia and found that, including this case, only 24 cases of Down's syndrome and acute leukemia have been reported with chromosome banding analysis. Twenty-three of the patients had a trisomy 21 chromosome complement, whereas, one had a translocation. The types of acute leukemia included acute myeloblastic leukemia, acute myelomonocytic leukemia, acute monoblastic leukemia, acute lymphoblastic leukemia, and erythroleukemia. Only three cases had chromosomes missing from the leukemic cells. Sixteen of the 24 patients had extra chromosomes in their malignant cells. Chromosomes #8 and #21 were extra in six cases each and chromosomes #19 and #22 were extra in four cases each. Chromosome rearrangements were observed in nine cases. Three of the nine cases had partial deletion of the long arm of chromosome #6. Cases of Down's syndrome with acute leukemia need to be reported with high-resolution chromosome banding of the leukemia cells. There is as yet no clear chromosome clue as to the precise basis of the etiologic association between Down's syndrome and acute leukemia.

  View details for Web of Science ID A1986A337200001

  View details for PubMedID 2936445

• CYTOGENETIC AND IMMUNOPHENOTYPIC ANALYSIS OF CELL-LINES ESTABLISHED FROM PATIENTS WITH T-CELL LEUKEMIA LYMPHOMA BLOOD Smith, S. D., Morgan, R., Link, M. P., McFall, P., Hecht, F. 1986; 67 (3): 650-656

  Abstract

  Cell lines were established from five patients with T cell malignancies. Two patients had T cell lymphoblastic lymphoma (T-LL), whereas three patients had T cell acute lymphoblastic leukemia (T-ALL). Both T-LL cell lines expressed cell surface antigens characteristic of midthymocytes (Leu 2, 3, 6+). One T-ALL cell line also expressed this immunophenotype, one expressed suppressor/cytotoxic antigens (Leu 2+; Leu 3, 6-), and one expressed antigens of a mature but uncommitted T cell (Leu 4+; Leu 2, 3, 6-). Cytogenetic analysis showed that each cell line had 46 chromosomes with pseudodiploidy. The three T-ALL cell lines had only a few chromosome changes; one cell line had one deletion, another had two deletions, and the third had a translocation and two deletions (including loss of part of 9p). In comparison, both T-LL cell lines had complex chromosome changes, including most notably a rearrangement of band 14q11.2. The immunophenotypes and chromosome breakpoints showed patterns of interlock between the T-LL and T-ALL cell lines because common abnormalities occurred at six distinct chromosome sites. Cell lines with limited and specific chromosomal abnormalities are important because they can provide the basic material for molecular genetic studies that could elucidate the genetic mechanisms involved in neoplasia.

  View details for Web of Science ID A1986A373200015

  View details for PubMedID 3004618

• LYMPHOBLASTIC LYMPHOMA - AN IMMUNOPHENOTYPE STUDY OF 26 CASES WITH COMPARISON TO T-CELL ACUTE LYMPHOBLASTIC-LEUKEMIA BLOOD Weiss, L. M., BINDL, J. M., Picozzi, V. J., Link, M. P., Warnke, R. A. 1986; 67 (2): 474-478

  Abstract

  A series of 26 lymphoblastic lymphomas (LLs) and 13 T cell acute lymphoblastic leukemias (ALLs) were investigated using a battery of monoclonal antibodies applied to tissue frozen sections. Twenty-one of the LLs were of T lineage. All but one of the T cell LLs were of immature thymic phenotype, mostly corresponding to stage II cortical thymocyte development. The T cell LLs expressed Leu-1 in 100%, Leu-4 and Leu-9 in 95%, and Leu-5 in 85% of the cases. The high percentage of Leu-4 expression in this series is probably due to detection of cytoplasmic antigen with our methods. One LL was of pre-B or B cell and two cases were of common ALL phenotype. Two cases were of undefined phenotype, expressing markers of both B and T cell differentiation. Pediatric cases showed a greater tendency toward T cell phenotype than did adult cases. The cases of T cell ALL were immunophenotypically similar to the cases of T cell LL but showed a tendency toward a more immature phenotype.

  View details for Web of Science ID A1986AZK8500035

  View details for PubMedID 3080041

• MEDIASTINAL NONLYMPHOBLASTIC LYMPHOMAS IN CHILDREN - A CLINICOPATHOLOGICAL STUDY JOURNAL OF CLINICAL ONCOLOGY Bunin, N. J., Hvizdala, E., Link, M., Callihan, T. R., HUSTU, H. O., Wharam, M., Warnke, R. A., Berard, C. W., Murphy, S. B. 1986; 4 (2): 154-159

  Abstract

  The records of 25 pediatric patients with mediastinal nonlymphoblastic lymphoma (NLBL) were reviewed. These patients comprise approximately 5% of all patients with non-Hodgkin's lymphoma (NHL) in the pediatric age group. There were 15 females and ten males. The median age was 13.5 years (range, 2 to 19). Most patients presented with symptoms attributable to a large mediastinal mass, and superior vena cava syndrome was a common feature. Disease was localized to the supradiaphragmatic area in 17 patients (71%) at diagnosis. Pathologic review revealed 22 of these lymphomas to be diffuse histiocytic type in the Rappaport classification, and 20 were large-cell immunoblastic type in the Working Formulation. Treatment regimens were not uniform, but included multiagent chemotherapy in 23 patients and radiation to the mediastinum in 20 patients. Twenty-three patients (92%) attained a complete remission (CR). Of these, 17 (74%) remain disease-free 13 to 65 months from diagnosis (median, 43 months). No CNS relapses have been observed. Mediastinal NLBL in the pediatric age group has distinctive clinicopathologic features that warrant special consideration in the design of treatment protocols.

  View details for Web of Science ID A1986AZC1500006

  View details for PubMedID 3753718

• Adjuvant therapy in the treatment of osteosarcoma. Important advances in oncology Link, M. P. 1986: 193-207

  View details for PubMedID 3330533

• CONSERVATIVE MANAGEMENT OF TESTICULAR ENDODERMAL SINUS TUMOR IN CHILDHOOD JOURNAL OF UROLOGY Carroll, W. L., Kempson, R. L., GOVAN, D. E., Freiha, F. S., Shochat, S. J., Link, M. P. 1985; 133 (6): 1011-1014

  Abstract

  Endodermal sinus tumor is the most common testicular neoplasm in childhood. The management of children with this neoplasm remains controversial. We have treated prospectively 5 children with stage I endodermal sinus tumor with limited surgery and no adjuvant therapy. The median patient age at diagnosis was 21 months (range 5 to 24 months). All children underwent an inguinal orchiectomy with high ligation of the spermatic cord. Retroperitoneal node dissection was not performed in any case and no child received adjuvant chemotherapy or radiation therapy. All patients were well without evidence of recurrent disease at a median followup of 46 months (range 19 to 72 months). Because these tumors usually are localized at the time of diagnosis, rarely spread to the retroperitoneal nodes and have a biological marker in most cases, and because good salvage chemotherapy is available for patients with relapse, we believe that nonmetastatic testicular endodermal sinus tumors in children can be managed with radical orchiectomy alone. Retroperitoneal node dissection is not necessary and adjuvant therapy is not indicated if markers return to normal. Further treatment should be reserved for the rare child with relapse.

  View details for Web of Science ID A1985AJN3700020

  View details for PubMedID 2582151

• NEURO-BLASTOMA IN INFANTS - WHEN IS THERAPY NECESSARY Amylon, M. D., Link, M. P., Perrine, S. P., Shochat, S. J., Donaldson, S. S., Glader, B. E. INT PEDIATRIC RESEARCH FOUNDATION, INC. 1985: A257–A257

  View details for Web of Science ID A1985AEU1800880

• ABNORMAL HELPER - SUPPRESSOR T-CELL RATIO IN THE STAFF OF A PEDIATRIC HOSPITAL NEW ENGLAND JOURNAL OF MEDICINE Somma, C., Miller, J. J., Silverman, E. D., Link, M. P. 1985; 312 (24): 1573-1574

  View details for Web of Science ID A1985AJX7300013

  View details for PubMedID 3158815

• LEUKEMIA WITH DOWNS-SYNDROME - TRANSLOCATION BETWEEN CHROMOSOME-1 AND CHROMOSOME-19 IN ACUTE MYELOMONOCYTIC LEUKEMIA FOLLOWING TRANSIENT CONGENITAL MYELOPROLIFERATIVE SYNDROME BLOOD Morgan, R., Hecht, F., Cleary, M. L., Sklar, J., Link, M. P. 1985; 66 (6): 1466-1468

  Abstract

  A girl with Down's syndrome was born with a myeloproliferative disorder. The child had spontaneous regression of the myeloproliferation, with acute leukemia developing at a later date. Morphologic, cytochemical, immunologic, and immunoglobulin gene configuration studies all supported the diagnosis of acute nonlymphocytic leukemia. High-resolution chromosome studies revealed that the leukemic cells consistently contained a translocation between chromosomes 1 and 19: der(19)t(1;19)(q25;p13). Spontaneous regression of the transient myeloproliferative syndrome of the newborn with Down's syndrome may not always be permanent, and the transient myeloproliferative syndrome may sometimes represent an early sign of acute nonlymphocytic leukemia.

  View details for Web of Science ID A1985AWG8500040

  View details for PubMedID 2415189

• DISCORDANCE BETWEEN SURFACE AND CYTOPLASMIC EXPRESSION OF THE LEU-4 (T3) ANTIGEN IN THYMOCYTES AND IN BLAST CELLS FROM CHILDHOOD T-LYMPHOBLASTIC MALIGNANCIES JOURNAL OF CLINICAL INVESTIGATION Link, M. P., Stewart, S. J., Warnke, R. A., Levy, R. 1985; 76 (1): 248-253

  Abstract

  We have examined the expression of the Leu-4 (T3) antigen on the cell surface and in the cytoplasm of blast cells from 23 patients with T cell acute lymphoblastic leukemia and T cell lymphoblastic lymphoma. In the majority of cases (17), the Leu-4 antigen was absent from the cell surface; however, in 16 of these 17 cases, blast cells demonstrated cytoplasmic expression of Leu-4. This discordance between surface and cytoplasmic expression of Leu-4 was also found in thymocytes and appeared to be restricted to Leu-4, in that tests of other T cell antigens rarely revealed discordance between surface and cytoplasmic expression. To study further the cytoplasmic determinant identified by anti-Leu-4 in malignant T lymphoblasts, immunoprecipitation studies were performed that utilized biosynthetic labeling of established T cell lines derived from T lymphoblastic malignancies. By one-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis, identical Leu-4 polypeptide families were immunoprecipitated from surface Leu-4+ and surface Leu-4-/cytoplasmic Leu-4+ cell lines. Because T lymphoblastic malignancies represent proliferations of immature T cells, and because the cases studied demonstrated surface phenotypes corresponding to all of the proposed stages of T cell ontogeny, it appears that cytoplasmic expression of Leu-4 occurs early in T cell development. The reason for the failure of these immature T cells to transport the Leu-4 molecule to their surface remains to be elucidated.

  View details for Web of Science ID A1985AMF6100035

  View details for PubMedID 2410458

• NON-HODGKINS LYMPHOMA IN CHILDREN PEDIATRIC CLINICS OF NORTH AMERICA Link, M. P. 1985; 32 (3): 699-720

  Abstract

  The childhood non-Hodgkin's lymphomas (NHL) are histologically, immunologically, and clinically a heterogeneous group of diseases. Recent advances in our understanding of NHL have demonstrated the similarities between childhood NHL and childhood acute lymphoblastic leukemia (ALL). Treatment strategies utilizing systemic chemotherapy and modeled after successful treatment programs for ALL have resulted in a dramatic improvement in prognosis for children with NHL, and the majority of affected children are now curable.

  View details for Web of Science ID A1985AKA8800011

  View details for PubMedID 3889803

• ACUTE LEUKEMIAS ASSOCIATED WITH THE 4-11 CHROMOSOME-TRANSLOCATION HAVE REARRANGED IMMUNOGLOBULIN HEAVY-CHAIN GENES BLOOD Crist, W. M., Cleary, M. L., GROSSI, C. E., Prasthofer, E. F., HEGGIE, G. D., Omura, G. A., Carroll, A. J., Link, M. P., Sklar, J. 1985; 66 (1): 33-38

  Abstract

  Studies of acute leukemia with the 4;11 translocation have yielded conflicting results regarding the lineage of the cell of origin in this disease. To investigate this issue further, we have examined the state of immunoglobulin genes in tumor cells from two affected patients, immunophenotyped their leukemic cells using a number of monoclonal antibody reagents with specificities for lymphoid or myelomonocytic antigens, and examined the malignant cells by electron microscopy. DNA was extracted from leukemic bone marrow cells and hybridized with radiolabeled DNA fragment probes specific for the constant region of immunoglobulin heavy chain and kappa and lambda light chain genes. Autoradiographs revealed rearrangement of both allelic heavy chain genes, but a germline configuration of light chain genes in both cases. Surface marker analysis showed that blasts from both patients expressed HLA-DR and the myeloid antigens Leu-M1, 1C2, 2D1, and 4B3, but lacked common acute lymphocytic leukemia antigen or T antigens. Furthermore, they did not have sheep erythrocyte receptors nor did they express surface or cytoplasmic immunoglobulin or B cell precursor determinants. Electron microscopy analysis showed that blast cells from patient 1 exhibited numerous monoribosomes, polyribosomes, and isolated strands of rough endoplasmic reticulum in their cytoplasm. These ultrastructural features are characteristic for both common acute lymphocytic leukemia and pre-B-ALL cells, but not for T-ALL or acute myelogenous leukemia cells. Peroxidase was undetectable in cells from both patients. Our study suggests that this disorder represents a unique subtype of leukemia. The cell of origin may be an early B cell progenitor that shares certain surface antigens with myeloid cells or a stem cell with the potential for both lymphoid and myelomonocytic differentiation.

  View details for Web of Science ID A1985AMF5400005

  View details for PubMedID 3159445

• IMMUNOLOGICAL SELECTION OF HEMATOPOIETIC PRECURSOR CELLS UTILIZING ANTIBODY-MEDIATED PLATE BINDING (PANNING) BLOOD Greenberg, P. L., Baker, S., Link, M., Minowada, J. 1985; 65 (1): 190-197

  Abstract

  We utilized the property of antibody adherence to plastic to separate and obtain enriched fractions of human myeloid (CFU-GM), erythroid (BFU-E) and pluripotent (CFU-GEMM) hemopoietic precursor cells. Nonadherent buoyant human marrow cells coated with mouse anti-human HLA-DR monoclonal antibody (Mc ab), an anti-pan T lymphocyte Mc ab (Leu 1/17F12) or a granulocyte--monocyte-specific Mc ab (MCS2) were incubated on polystyrene Petri plates coated with affinity purified goat anti-mouse immunoglobulin G (IgG). Cells bound to the coated plates and nonbound cells were separately recovered ("panned") by differential elution. Analysis of the nonadherent buoyant marrow cells demonstrated 12% to possess HLA-DR, 6% T, 40% MCS2 antigens on their surface by indirect immunofluorescence (IMF). After panning, 15% +/- 8%, 14% +/- 4% and 8% +/- 6% cells were plate-bound by their respective antibodies, demonstrating differing binding efficiencies. A substantial degree of purity of the recovered cell fractions was shown for bound 74% +/- 6% and 75% +/- 5% IMF positive cells) and nonbound cells (3% +/- 1% and 0.1% +/- 0.8% positive cells) coated with anti-HLA-DR or anti-T Mc ab respectively, with lesser purity for MCS2 panned cells. Seventy-three percent to 126% CFU recovery was noted, with a sevenfold enrichment of the HLA-DR bound cells for CFU-GM and CFU-GEMM, and 3.5-fold enrichment for BFU-E. Sequential panning, obtaining T nonbound-DR bound-surface immunoglobulin nonbound fractions, resulted in tenfold CFU-GM enrichment (107/10(4) cells, approximately equal to 1/100). Anti-MCS2 antibody was ineffective for panning, but use of this antibody in fluorescence-activated cell sorting (FACS) indicated the absence of the MCS2 antigen on the vast majority of CFU-GM. This study describes a relatively rapid and inexpensive method for obtaining enriched antigenically defined hemopoietic precursors in high yield. These techniques should prove useful for more clearly evaluating cellular and humoral interactions with hemopoietic precursor cells.

  View details for Web of Science ID A1985TZ40000028

  View details for PubMedID 3855263

• ACUTE NONLYMPHOCYTIC LEUKEMIA DEVELOPING DURING THE COURSE OF EWINGS-SARCOMA MEDICAL AND PEDIATRIC ONCOLOGY Link, M. P., Donaldson, S. S., Kempson, R. L., Wilbur, J. R., Glader, B. E. 1984; 12 (3): 194-200

  Abstract

  Two children with Ewing's sarcoma developed acute nonlymphocytic leukemia (ANLL) during the course of their illness. One patient developed ANLL after apparently successful treatment of his primary malignancy with radiation therapy and multiagent chemotherapy. In the second patient, acute leukemia developed before the administration of radiotherapy or systemic chemotherapy. The development of secondary ANLL after Ewing's sarcoma has been reported only twice previously, most likely representing a therapy-induced complication. The occurrence of ANLL in Patient 2 prior to therapy suggests that these two disorders may have a more than treatment-related association. Close follow-up of long-term survivors of Ewing's sarcoma with surveillance for secondary acute leukemia is advised.

  View details for Web of Science ID A1984SW62300009

  View details for PubMedID 6727775

• BIOCHEMICAL AND RADIOLOGIC-DIAGNOSIS OF LEUKEMIA IN A HEMATOLOGICALLY NORMAL-CHILD Perrine, S. P., Parker, B. R., SILVERMAN, F. N., BACKER, K., Link, M. P., Zwerdling, T., Glader, B. E. SLACK INC. 1984: A104–A104

  View details for Web of Science ID A1984RZ82200617

• PAN-LEUKOCYTE MONOCLONAL ANTIBODY-L3B12 - CHARACTERIZATION AND APPLICATION TO RESEARCH AND DIAGNOSTIC PROBLEMS AMERICAN JOURNAL OF CLINICAL PATHOLOGY Wood, G. S., Link, M., Warnke, R. A., Dilley, J., Levy, R. 1984; 81 (2): 176-183

  Abstract

  In this report, the authors describe a murine anti-human monoclonal antibody, L3B12, which defines a pan-leukocyte cell surface antigen of approximately 180,000 m.w. Extensive screening against a variety of tissues indicates that L3B12 is sensitive and specific for leukocytes, related cells of bone marrow lineage, and their corresponding neoplasms. Unlike many lymphoid antigens that are not detectable following routine fixation and embedding, those recognized by L3B12 and related antibodies are variably preserved. L3B12 has proven useful in studying the antigen expression of normal leukocytic elements, lymphomas, and related disorders, and in enriching or depleting leukocytes from heterogeneous cell populations. From a diagnostic standpoint, L3B12 staining of tissue sections or cell suspensions is useful for distinguishing large cell lymphomas from undifferentiated carcinomas and in distinguishing lymphomas and leukemias from other small round cell tumors of childhood.

  View details for Web of Science ID A1984SD84900005

  View details for PubMedID 6364781

• PROGNOSTIC-SIGNIFICANCE OF COMPLETE SURGICAL RESECTION OF PULMONARY METASTASES IN PATIENTS WITH OSTEOGENIC-SARCOMA - ANALYSIS OF 32 PATIENTS JOURNAL OF CLINICAL ONCOLOGY Goorin, A. M., DELOREY, M. J., Lack, E. E., Gelber, R. D., Price, K., Cassady, J. R., Levey, R., Tapper, D., Jaffe, N., Link, M., Abelson, H. T. 1984; 2 (5): 425-431

  Abstract

  Between 1972 and 1981, 93 patients with extremity osteogenic sarcoma without detectable metastatic disease were treated with surgery and adjuvant chemotherapy. Fifty-two patients remain continuously free of disease. Thirty-two of the 41 patients who relapsed had pulmonary metastases only and 26 underwent thoracotomy to remove all metastatic disease. Complete resection was possible in 11 of 26 patients as defined by the removal of all macroscopic disease, no microscopic disease at resection margins, and no histologic evidence of pleural disruption by tumor. Nine of 11 patients are currently free of disease with a median duration of most recent remission of 42 months (range, 3-72 months). Four of these nine patients have had only one relapse. Only two of 15 patients with incomplete resection of metastatic disease defined by the above criteria are currently free of disease for 57 and 101 months. A significant difference in survival from initial relapse for patients made surgically free of disease using this stringent criteria was observed even when the result is stratified for time to first relapse and number of pulmonary nodules (p = 0.005). A subgroup of patients within the group undergoing thoracotomies who can be expected to have an improved survival has been defined.

  View details for Web of Science ID A1984SS13800012

  View details for PubMedID 6587016

• A UNIQUE HUMAN LYMPHOCYTE-B ANTIGEN DEFINED BY A MONOCLONAL-ANTIBODY HYBRIDOMA MEEKER, T. C., MILLER, R. A., Link, M. P., Bindl, J., Warnke, R., Levy, R. 1984; 3 (4): 305-320

  Abstract

  We produced a hybridoma designated 4G7 from a mouse immunized with chronic lymphocytic leukemia cells. The 4G7 hybridoma secretes an IgG1 antibody that is specific for normal and malignant B lymphocytes. Using dual color immunofluorescence staining, this antibody reacted with all immunoglobulin-positive cells but no T cells in normal peripheral blood. There was no detectable 4G7 antigen on monocytes, platelets, red cells, granulocytes, or phytohemagglutinin-activated T cells. When PBL were depleted of 4G7 positive cells and stimulated with pokeweed mitogen, secreted immunoglobulin levels fell to less than 10% of control values on Day 5 and less than 1% of control on Day 7. This antibody was reactive with 155 of 176 B lineage neoplasms on which it was screened. Thirty-five cases of myeloid or T-lymphoid malignancy were negative. Our studies show that the 4G7 antigen modulates in the presence of excess antibody. Free 4G7 antigen was not found circulating in human serum. The cell surface antigen identified by 4G7 was sensitive to pronase proteolysis but resistant to trypsin and chymotrypsin digestion. A comparison of 4G7 with other known B-cell antibodies indicates that the 4G7 antigen has not been previously identified. This antibody is of use for the identification of normal B lymphocytes, the study of B-cell differentiation, and the characterization of lymphoid malignancies.

  View details for Web of Science ID A1984AAF5100001

  View details for PubMedID 6441771

• THYROID-DYSFUNCTION AFTER RADIOTHERAPY IN CHILDREN WITH HODGKINS-DISEASE CANCER Constine, L. S., Donaldson, S. S., McDougall, I. R., Cox, R. S., Link, M. P., KAPLAN, H. S. 1984; 53 (4): 878-883

  Abstract

  Thyroid function was measured in 119 children, 16 years of age or less, after radiotherapy (XRT) for Hodgkin's disease. Thyroid abnormalities developed in 4 of 24 children (17%) who received 2600 rad or less, and in 74 of 95 children (78%) who received greater than 2600 rad to the cervical area, including the thyroid. The abnormality in all but three (one with hyperthyroidism and two with thyroid nodules) included the development of elevated levels of thyroid stimulating hormone (TSH). Age, sex, and administration of chemotherapy were not significant factors in the development of thyroid dysfunction. All children had lymphangiograms (LAG) and no time relationship was noted between thyroid dysfunction and LAG-XRT interval. The mean interval from radiotherapy to documented thyroid dysfunction was 18 months in the low-dose group and 31 months in the high-dose group, with most patients becoming abnormal within 3 to 5 years. Of interest was a spontaneous return of TSH to within normal limits in 20 children and substantial improvement in another 7. This study confirms the occurrence of dose-related occult hypothyroidism in children following external irradiation of the neck.

  View details for Web of Science ID A1984SB64800010

  View details for PubMedID 6692289

• IMMUNE THROMBOCYTOPENIA ASSOCIATED WITH ACUTE NONLYMPHOCYTIC LEUKEMIA JOURNAL OF PEDIATRICS Amylon, M. D., Link, M. P., Glader, B. E. 1984; 105 (5): 776-778

  View details for Web of Science ID A1984TR54000020

  View details for PubMedID 6502309

• MONOCLONAL-ANTIBODY AND ENZYMATIC PROFILES OF HUMAN-MALIGNANT LYMPHOID-T CELLS AND DERIVED CELL-LINES CANCER RESEARCH Smith, S. D., Shatsky, M., Cohen, P. S., Warnke, R., Link, M. P., Glader, B. E. 1984; 44 (12): 5657-5660

  Abstract

  Recently, four distinct cell lines were established from patients whose malignancies had been defined by immunological and biochemical markers. Each patient had a distinct subtype of a T-cell cancer, and each possessed elevated adenosine deaminase and reduced nucleoside phosphorylase activity. Cell lines cultured in vitro possessed the same basic immunophenotype and biochemical enzyme activity as the patients' original malignant cells. In a direct comparison of the immunophenotype of the cell lines and the patients' malignant cells, full concordance existed for 48 of 52 paired antibody tests performed. However, when compared to the corresponding patient's sample, each cell line showed some minor changes in antigen expression or enzyme level. Antigen loss, de novo antigen expression, or elevated adenosine deaminase levels occurred in the cell lines, and these changes were stable on repeated analysis. While there was good general concordance between the patient's cancer and the established cell line, minor biological differences in the cell lines may reflect cellular maturation or subpopulation selection in vitro.

  View details for Web of Science ID A1984TU47100032

  View details for PubMedID 6437672

• IDENTIFICATION AND SIGNIFICANCE OF CELL MARKERS IN LEUKEMIA AND LYMPHOMA ANNUAL REVIEW OF MEDICINE Warnke, R. A., Link, M. P. 1983; 34: 117-131

  Abstract

  The identification of markers of human hematopoietic cell differentiation and function has revealed the nature of the proliferating cell in many lymphoid neoplasms and demonstrated marked phenotypic heterogeneity in traditional subgroups. Selected markers are described that define common subgroups of lymphoid leukemia and non-Hodgkin's lymphoma. The identification of cell markers has significant implications for accuracy of diagnosis, for predicting clinical characteristics, and for understanding the biology of these diseases.

  View details for Web of Science ID A1983QJ82600010

  View details for PubMedID 6407386

• CRANIAL NERVE INVOLVEMENT IN CHILDREN WITH LEUKEMIA AND LYMPHOMA JOURNAL OF CLINICAL ONCOLOGY PARYANI, S. B., Donaldson, S. S., Amylon, M. D., Link, M. P. 1983; 1 (9): 542-545

  Abstract

  Between 1965 and 1982, 52 children with acute lymphoblastic leukemia or non-Hodgkin's lymphoma were found to have central nervous system involvement of their disease. Of this group, 20 developed clinically apparent cranial nerve paresis or palsy. The cranial nerve most frequently affected was No. VII. With therapy, 16 of the patients had objective control of their central nervous system disease. Among these 16 patients, cranial nerve palsies resolved completely in 14, and only two children were left with residual cranial nerve dysfunction. Seven patients received intrathecal chemotherapy before radiation therapy was instituted in an attempt to control their cranial nerve palsies. Cranial nerve palsy resolved in only two of these seven patients. However, the addition of whole-brain irradiation in the remaining five patients reversed cranial nerve dysfunction in four of them. The combination of intrathecal chemotherapy and central nervous system irradiation was successful in reversing cranial nerve dysfunction in 11 of 13 patients in whom central nervous system disease was ultimately controlled. As cranial nerve dysfunction is associated with distressing signs and symptoms, the combination of central nervous system irradiation and intrathecal chemotherapy is important palliative therapy to initiate promptly. Intrathecal therapy alone appears to be inadequate therapy for prompt and durable reversal of symptoms in this group of patients.

  View details for Web of Science ID A1983RK55800005

  View details for PubMedID 6583324

• CUTANEOUS LYMPHOBLASTIC LYMPHOMA WITH PRE-B MARKERS BLOOD Link, M. P., Roper, M., Dorfman, R. F., Crist, W. M., COOPER, M. D., Levy, R. 1983; 61 (5): 838-841

  Abstract

  Two children with cutaneous convoluted lymphoblastic lymphoma are reported. Malignant cells from both patients contained cytoplasmic Mu heavy chains characteristic of pre-B-cells and expressed CALLA and la antigens as well. Most cases of convoluted lymphoblastic lymphoma are T-cell-derived neoplasms. The non-T, non-B phenotype found in these two children demonstrates that histology does not necessarily predict immunophenotype. The association of the pre-B phenotype with cutaneous lymphoma has not been previously reported, but may represent a unique clinical-histopathologic-immunologic entity that occurs in young children.

  View details for Web of Science ID A1983QN28600003

  View details for PubMedID 6600948

• METHOTREXATE-INDUCED RENAL IMPAIRMENT - CLINICAL-STUDIES AND RESCUE FROM SYSTEMIC TOXICITY WITH HIGH-DOSE LEUCOVORIN AND THYMIDINE JOURNAL OF CLINICAL ONCOLOGY Abelson, H. T., FOSBURG, M. T., Beardsley, P., Goorin, A. M., Gorka, C., Link, M., Link, D. 1983; 1 (3): 208-216

  Abstract

  Four separate groups of patients have been studied: (1) The effect of high-dose methotrexate (MTX) administration on glomerular filtration rate was determined by pre- and posttreatment inulin and creatinine clearances in nine patients. Measurements were made prior to and 24-40 hr after drug administration. Inulin and creatinine clearances both decreased a mean of 43%. No signs of systemic toxicity occurred. (2) Three other patients given high-dose courses of MTX developed MTX toxicity. Their creatinine clearance decreased an average of 61%. (3) In a separate group of five patients undergoing weekly MTX treatment, comparison of serum MTX pharmacokinetics with and without alkalinization of the urine demonstrated no significant difference in peak serum MTX levels or serum MTX decay. (4) Eight additional patients with severe renal dysfunction secondary to MTX were treated with increased doses of leucovorin and a continuous infusion of thymidine (8 g/m2/day) once renal failure was recognized. When high-dose leucovorin and thymidine were begun 48-72 hr after the MTX infusion, severe toxicity in the form of leukopenia, thrombocytopenia, diffuse mucositis, stomatitis, or skin rash was averted. We concluded the following: (1) high-dose MTX causes a subclinical decrease in glomerular filtration rate with each administration, even in nontoxic courses; (2) alkalinization of the urine with sodium bicarbonate does not alter plasma MTX decay, while volume expansion (hydration) is maintained constant; and (3) rigorous monitoring of serum creatinine and serum MTX levels 24-48 hr after MTX administration allows for the institution of rescue measures, including leucovorin and thymidine, which will abort the systemic toxicity that accompanies MTX-induced renal failure.

  View details for Web of Science ID A1983QW73300007

  View details for PubMedID 6607976

• A SINGLE MONOCLONAL-ANTIBODY IDENTIFIES T-CELL LINEAGE OF CHILDHOOD LYMPHOID MALIGNANCIES BLOOD Link, M., Warnke, R., Finlay, J., Amylon, M., Miller, R., Dilley, J., Levy, R. 1983; 62 (4): 722-728

  Abstract

  Immunophenotyping studies with monoclonal antibodies have revealed the heterogeneity of childhood acute lymphoblastic leukemia (ALL) and non-Hodgkin's lymphoma (NHL). The lymphoid malignancies of T-cell lineage are particularly heterogeneous and, until now, no single monoclonal antibody has been found to identify all cases of T-ALL and T-NHL. A monoclonal antibody, 4H9, recognizes an antigen of 40,000 molecular weight on normal and malignant T cells. Thirty-six cases of childhood T-ALL and T-NHL were tested, and in all cases, the malignant blast cells were reactive with 4H9, whereas malignant cells from 61 cases of non-T ALL and NHL were not reactive with 4H9. Monoclonal antibody 4H9 is a sensitive and specific reagent for the identification of childhood T-cell ALL and NHL and should be extremely useful in immunophenotyping studies of lymphoid malignancies.

  View details for Web of Science ID A1983RK80600002

  View details for PubMedID 6603882

• High-dose methotrexate in osteogenic sarcoma. National Cancer Institute monograph Jaffe, N., Link, M. P., Cohen, D., TRAGGIS, D., FREI, E., Watts, H., Beardsley, G. P., Abelson, H. T. 1981: 201-206

  Abstract

  From 1972 to 1979, high-dose methotrexate (HDMTX) and 3 adjuvant regimens were used at the Sidney Farber Cancer Institute and Children's Hospital Medical Center. In the first regiment, HDMTX was used alone; the second, HDMTX and adriamycin, and the third, weekly courses of HDMTX and combination. Actuarial disease-free survival achieved with these regimens in patient with local control of the primary lesion varied from 42 to 75% at 3 years. This compared favorably with historical control patients, of whom 50% were free of disease at 6 months and only 20% at 12 months. Among 41 patients with established pulmonary metastases, 14 were alive and free of disease from more than 4 to over 60 months. The most efficacious method of administering HDMTX was a weekly schedule which produced an overall response rate of 48% in the treatment of pulmonary metastases and primary tumor in patients previously not exposed to HDMTX. Urinary alkalinization was not a standard procedure, and investigations failed to demonstrate any significant effect of alkalinization on HDMTX pharmacokinetics.

  View details for PubMedID 6975438

• HIGH-DOSE METHOTREXATE IN OSTEOGENIC-SARCOMA ADJUVANT CHEMOTHERAPY AND LIMB SALVAGE RESULTS CANCER TREATMENT REPORTS Jaffe, N., Goorin, A., Link, M., Watts, H., Frei, E., VAWTER, G., Fellows, K. E., Beardsley, G. P., Abelson, H. T. 1981; 65: 99-106

  Abstract

  This communication provides a description and update of the three adjuvant regimens utilized at the Sidney Farber Cancer Institute. The disease-free survivals are: Study I--42% at 4 years; Study II--58% at 3 years; and Study III--currently 78%. In the limb salvage experience, among the evaluable patients, 6 of 12 treated with preoperative chemotherapy are disease free (median 32 months) and 12 of 14 (86%) treated without preoperative chemotherapy are disease free (median 13 months).

  View details for Web of Science ID A1981NC61200015

  View details for PubMedID 6948612

• FETAL-LIKE ERYTHROPOIESIS DURING RECOVERY FROM TRANSIENT ERYTHROBLASTOPENIA OF CHILDHOOD (TEC) PEDIATRIC RESEARCH Link, M. P., Alter, B. P. 1981; 15 (7): 1036-1039

  Abstract

  Fetal-like erythropoiesis frequently accompanies marrow stress conditions such as Diamond-Blackfan syndrome and aplastic anemia. In contrast, patients with transient erythroblastopenia of childhood have erythrocytes which lack fetal characteristics at the time of diagnosis. This report describes nine children with transient erythroblastopenia of childhood in whom transient, fetal-like erythropoiesis was observed during the period of recovery. These patients initially presented with anemia, reticulocytopenia, erythrocytes of normal size for age, low levels of fetal hemoglobin, and i-antigen. During the recovery period, however, erythrocytes manifested one or more fetal characteristics. These included an increased fetal hemoglobin (in three of five patients), the presence of i-antigen (in four of six patients), and macrocytosis (in seven of nine patients). These fetal characteristics persisted more than 2 wk after the reticulocyte count returned to normal. Within one year from diagnosis, red blood cells contained no fetal characteristics.

  View details for Web of Science ID A1981LV28000012

  View details for PubMedID 7254949

• NON-HODGKINS LYMPHOMA IN CHILDHOOD CLINICS IN HAEMATOLOGY Weinstein, H. J., Link, M. P. 1979; 8 (3): 699-716

  View details for Web of Science ID A1979JA48500011

  View details for PubMedID 498600