Shifra Ash

The predictive potential of molecular detection in the nonmetastatic Ewing family of tumors

Tumors in the Ewing family (EFTs) are the second most common bone tumors in children and adolescents. Despite aggressive chemotherapy, one‐third of patients with localized tumor still may develop recurrences. This implies that not all tumor cells are eradicated and that the patients may have a level of residual disease. EFTs are characterized by specific chromosomal translocations that result in chimeric transcripts that can be detected with reverse transcriptase‐polymerase chain reaction (RT‐PCR) analysis.

Telomere length is a prognostic factor in neuroblastoma

Maintenance of telomeres, in most instances by reactivation of telomerase, is obligatory for the indefinite proliferation of tumor cells. The objective of this study was to evaluate telomere length and telomerase activity (TA) as markers for progression and prognosis in neuroblastoma.

A distinct subtype of M4/M5 acute myeloblastic leukemia (AML) associated with t(8:16)(p11:p13), in a patient with the variant t(8:19)(p11:q13)—Case report and review of the literature

Acute myeloblastic leukemia (AML) with t(8:16) or its variant t(8:V) has been rarely reported. A high proportion of patients are infants and children, often with a bleeding tendency and disseminated intravascular coagulopathy (DIC). Only one-third of the de novo patients remain in the first complete remission following multiagent chemotherapy and bone marrow transplantation (BMT). Morphocytochemically, the disorder is classified as an M5, M4, or M4/M5 variant. In the presented case, with the variant t(8:19)(p11:q13), comprehensive light and electron microscopic blast cell characterization showed monocytic and granulocytic features compatible with the M4 subtype (on the monocytic predominance range of the French-American-British classification scale). Although hemophagocytosis, one of the hallmarks of the disease, was rare in our patient, numerous autophagic vacuoles were present. Immuno- and genotyping showed a myelomonocytic phenotype with no evidence of early progenitor antigen expression or mixed leukemia. These results and those of previous reports support the high specificity of t(8:16) or its variants to the unique M4/M5 type leukemia and the role of a gene on 8p11 in this specific transformation.

Colorectal carcinoma in childhood: a retrospective multicenter study.

Objectives:Colorectal carcinoma, a common adult malignancy, has an estimated childhood incidence of 0.3 to 1.5/million in Western countries and 0.2/million in Israel. Diagnosis is difficult because adult screening measures are unfeasible in children. The tumor is frequently associated with predisposing genetic factors, aggressive biological behavior, and poor prognosis. The aim of this multicenter study was to document the clinical profile, treatment and prognosis of colorectal carcinoma in children in Israel. Patients and Methods:The clinical, laboratory, therapeutic, and prognostic parameters of all 7 children from 4 medical centers in Israel who were diagnosed with colorectal carcinoma over a 25-y period were reviewed. Results:Patients presented with rectal bleeding (4 of 7), abdominal pain (2 of 7), and abdominal distension (2 of 7). Average time to diagnosis was 6 months. Six patients underwent surgery (1 refused), and 5 received chemotherapy. Histopathological studies showed poorly differentiated mucinous adenocarcinoma, signet-ring type, in 4 cases, moderately differentiated adenocarcinoma in 2, and well-differentiated carcinoma in 1. Three patients died of the disease, 2 shortly after diagnosis. One patient with recurrent metastatic disease was lost to follow-up. Conclusion:Colorectal carcinoma in children is characterized by aggressive tumor behavior and delayed diagnosis, resulting in a worse prognosis than in adults. Heightened physician awareness of the possibility of this disease in children, with special attention to adolescents with predisposing factors and rectal bleeding, could help to improve outcome.

Short telomeres: a novel potential predictor of relapse in Ewing sarcoma.

Purpose: Despite advances in therapy, >50% of patients with Ewing sarcoma will relapse. The current prognostic factors are not optimal for risk prediction. Studies have shown that telomere length could predict outcome in different malignancies. Our aim was to evaluate whether telomere length could be a better prognostic factor in Ewing sarcoma and correlate the results with clinical variables, outcome, and chromosomal instability. Experimental Design: Telomere length was determined in the primary tumor and peripheral blood of 32 patients with Ewing sarcoma. Chromosomal instability was evaluated by combining classical cytogenetics, comparative genomic hybridization and random aneuploidy. Telomere length was correlated to clinical variables, chromosomal instability, and outcome. Results: In 75% of the tumors, changes in telomere length, when compared with the corresponding peripheral blood lymphocytes, were noted. The majority of changes consisted of a reduction in telomere length. Patients harboring shorter telomeres had a significantly adverse outcome (P = 0.015). Chromosomal instability was identified in 65% of tumors, significantly correlating with short telomeres (P = 0.0094). Using multivariate analysis, telomere length remained the only significant prognostic variable (P = 0.034). Patients with short telomeres had a 5.3-fold risk of relapse as compared to those with unchanged or longer telomeres. Conclusion: We have shown that tumors with telomere length reduction result in genomic instability. In addition, telomere length reduction was the only significant predictor of outcome. We suggest that reduction of telomere length in tumor cells at diagnosis could serve as a prognostic marker in Ewing sarcoma.

TEL-AML1 FUSION TRANSCRIPT DESIGNATES A FAVORABLE OUTCOME WITH AN INTENSIFIED PROTOCOL IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA

TEL-AML1 fusion transcript designates a favorable outcome with an intensified protocol in childhood acute lymphoblastic leukemia

Home intravenous antibiotic treatment for febrile episodes in immune-compromised pediatric patients.

The purpose of this work was to assess the feasibility of home intravenous antibiotic treatment (HIAT) for febrile episodes in immune-compromised (neutropenic, splenectomized), low-risk pediatric patients. Thirty hematology-oncology patients who presented to our emergency room from January 1993 to January 1995 and who suffered from a febrile episode and were considered at low risk for septic complications were immediately discharged on HIAT. Patients were followed for at least 3 weeks after recovery. Patients and parents were retrospectively questioned about adverse effects and about their degree of satisfaction with home treatment. Patients who required hospitalization during this period were considered unresponsive to HIAT and were analyzed for causes and adverse effects. Thirteen out of 60 (22%) febrile episodes, or eight out of 42 (19%) episodes of fever and neutropenia eventually led to hospitalization. Pseudomonas species infections were associated with the highest rate of unresponsiveness (88%). A central venous catheter infection developed in two cases following HIAT (two cases out of 640 days of therapy). No other complications were identified. No infection-related morbidity was observed. Patients and parents were highly satisfied with HIAT and wanted to use it again, if necessary. Immediate discharge on HIAT for low-risk pediatric immune-compromised patients suffering from a febrile episode is feasible, safe, and well accepted by patients and families. Patients who are found to have Pseudomonas infections should probably be hospitalized. Our results are preliminary and must be confirmed by a prospective, randomized trial before definite recommendations can be made.

Reduced levels of miR‐34a in neuroblastoma are not caused by mutations in the TP53 binding site

Neuroblastoma (NB) is the most common extracranial solid tumor in children below the age of 5 years. miR‐34a, located in chromosome band 1p36, has been recently implicated as a tumor suppressor gene in NB. In addition, it has been shown that miR‐34a is activated by TP53 by binding to a TP53 binding site upstream to the mature miR‐34a. We studied NB tumors from 57 patients for miR‐34a expression levels, 1p status, mutations in the TP53 coding region and mutations of the TP53 binding site. Reduced expression levels of miR‐34a were identified in tumors harboring 1p36.3 Loss (P = 0.028). No mutations were identified in the coding region of TP53, or in the TP53 binding site. Thus, mutations in the binding site are not an additional mechanism for the inactivation of miR‐34a in NB. Other regulatory mechanisms controlling miR‐34a expression and its relationship to TP53 should be further explored.

Consideration of strategies for hematopoietic cell transplantation

Bone marrow transplantation has been adoptively transferred from oncology to the treatment of autoimmune disorders. Along with extension of prevalent transplant-related concepts, the assumed mechanism that arrests autoimmunity involves elimination of pathogenic cells and resetting of immune homeostasis. Similar to graft versus tumor (GVT) reactivity, allogeneic transplants are considered to provide a better platform of immunomodulation to induce a graft versus autoimmunity reaction (GVA). It is yet unclear whether recurrence of autoimmunity in both autologous and allogeneic settings reflects relapse of the disease, transplant-associated immune dysfunction or insufficient immune modulation. Possible causes of disease recurrence include reactivation of residual host pathogenic cells and persistence of memory cells, genetic predisposition to autoimmunity and pro-inflammatory characteristics of the target tissues. Most important, there is little evidence that autoimmune disorders are indeed abrogated by current transplant procedures, despite reinstitution of both peripheral and thymic immune homeostasis. It is postulated that non-specific immunosuppressive therapy that precedes and accompanies current bone marrow transplant strategies is detrimental to the active immune process that restores self-tolerance. This proposition refocuses the need to develop strategies of immunomodulation without immunosuppression.

Additional chromosome 1q aberrations and der(16)t(1;16), correlation to the phenotypic expression and clinical behavior of the Ewing family of tumors

The cytogenetic hallmark of the Ewing family of tumors is t(11;22)(q24;q12) in its simple, complex or variant forms and/or its molecular equivalent EWS/FLI, EWS/ERG rearrangement. Additional secondary consistent chromosomal aberrations include the der(16)t(1;16) and, frequently, other chromosome 1q abnormalities leading to 1q overdosage. We studied whether these secondary cytogenetic changes are correlated to clinical features and phenotypic expression which may have a prognostic impact.Successful cytogenetic evaluation was performed in eight patients with a Ewing family tumor. In four of these, in addition to the primary aberration, chromosome 1q overdosage (including two with der(16)t(1;16)) was noted. Out of these four patients, two had metastatic disease at the time of evaluation, while in the other four, disease was localized. Morphologically, the tumors with the additional 1q aberration, revealed the pPNET subtype more frequently than the typical Ewing. They also expressed a higher degree of neural differentiation by neural marker immunocytochemistry, in comparison to tumors without the 1q aberration.Determination of the prognostic significance of this finding requires a longer follow-up with a larger group of patients.