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BACKGROUND Ifosfamide (IF) alone or combined with etoposide (ET) was reported to be effective in the treatment of patients with Ewing's sarcoma who relapsed after treatment with the VACA regimen, which consisted of vincristine (VC), actinomycin (AC), cyclophosphamide (CP), and doxorubicin (AD). The purpose of this article is to report the results achieved in a new neoadjuvant protocol in which IF and ET were added to the conventional VACA regimen and administered to patients with localized disease. METHODS In this study, eighty-two patients were treated between May 1988 and October 1991. Chemotherapy consisted of two induction cycles of VC/CP/AD followed by alternating cycles of VC/AD/CP, VC/IF/AC, IF/ET, and VC/CP/AC after local treatment. Twenty-two patients (27%) were treated with surgery only, 22 (27%) underwent surgery followed by radiation therapy, and 38 (46%) received radiotherapy only. RESULTS At a median follow-up of 6.7 years (range, 4-9 years), 43 patients (52%) remained continuously disease free, and 39 relapsed (34 with metastases, 4 with local recurrence and metastases, and 1 with a local recurrence). These results were similar to those obtained at the same institute in a previous neoadjuvant study (March 1983 and April 1988) that included 108 patients treated with the conventional 4-drug regimen. The 5-year disease free and overall survival in the current study were 54% and 59%, respectively, and in the first study were 50% and 56%, respectively. CONCLUSIONS The comparison of these two sequential studies, although not randomized, referred to homogeneous groups of patients observed at the same institution who were treated by the same medical team. No advantage was observed when IF and ET were added to the VACA regimen. Cancer 1998;82:1174-83. © 1998 American Cancer Society.

Clinicopathologic variables associated with a good histological response to primary chemotherapy in Ewing's sarcoma are identified. The histological response to preoperative chemotherapy in 243 cases of Ewing's sarcoma treated with neoadjuvant chemotherapy was analyzed in relation to different clinicopathological features (sex and age of the patients, tumor size, serum lactate dehydrogenase (LDH) levels, tumor site) and to the type and schedule of anticancer drugs delivered preoperatively according to three consecutive chemotherapy regimens. A higher rate of good responses was achieved with the use of ifosfamide and dactinomycin in addition to a conventional three-drug VAC regimen, suggesting that these drugs should be included from the beginning in neoadjuvant regimens for the treatment of Ewing's sarcoma. The analysis of event-free survival in 158 patients with a 4-year minimum follow-up confirmed that histological response to preoperative chemotherapy is a reliable predictor of outcome in Ewing's sarcoma.

Survival of children with acute lymphoblastic leukaemia (ALL) has increased considerably in recent years and data on the spontaneous growth and final height of these children are conflicting. Therefore, we analysed the longitudinal growth and final height in 52 survivors (33 females, 19 males) of childhood ALL. These children were diagnosed and treated in a single institution, all remained in first remission and were submitted to cranial irradiation with either 2400 or 1800 cGy. None of the patients received testicular or spinal irradiation. Median age at diagnosis was 4.2 (range 1.3–9.6) years in the first group (2400 cGy) and 3.9 (0.8–10.5) years in the second (1800 cGy). Standing height was measured at diagnosis, at the end of treatment (median 3.1 years after diagnosis), 6, 12, 24 months after the end of treatment, and finally at the completion of growth. In girls a significant decrease of mean height standard deviation score (SDS) during treatment and a catch up in growth after the end of therapy was followed by a second period of reduced growth. Mean final height SDS was significantly lower than the value at diagnosis in both groups of girls, but only in males treated with 2400 cGy. Mean overall loss in height SDS from diagnosis to final heigth was higher in females (−1.24) than in males (−0.40) (P=0.009). Females 4 years. An unchanged or improved final height was evident in 8 cases, the other 44 cases showed a final height decrease between −0.1 and −2 SDS in 36 and >-2 SDS in 8, 6 of whom were females 4 years. Only females treated at a younger age showed a final height lower than midparental height (−5.7±1.8 cm,P

Neoplastic invasion of the inferior vena cava due to renal tumors (especially Wilms' tumor) is uncommon in children. The tumor thrombus, according to the aggressiveness of the original neoplasm, can extend in diverse ways, obliterate the vascular lumen completely, and even reach the right atrium. The luminal thrombus might be accompanied by the involvement of the caval wall, which requires wide vascular resection. The purpose of this paper is to present our experience with 7 children, aged 18 months and 6 years, affected by caval invasion due to Wilms' tumor. Furthermore, the diagnostic techniques and the surgical treatment in simple caval thrombosis and in associated invasion of the caval wall are described.

In 1985, Stein et al. (Blood 66:848–858) described a large cell lymphoma consisting of activated lymphoid elements, expressing the Reed-Sternberg cell-associated antigen Ki-1 (CD30); this tumor has recently been included in the updated Kiel classification and has been termed anaplastic large cell lymphoma (ALCL). This report concerns 13 patients with previously untreated ALCL who were admitted to the Pediatric Hematology and Oncology Department of Bologna University between January 1983 and December 1989. Ten cases were diagnosed as common type ALCL, 1 as Hodgkin's-related ALCL and the remaining 2 as histiocyte-rich ALCL/lymphohistiocytic T-cell lymphoma. T-cell markers were present in 85% of the cases, and B pheno-type in the remaining 15%. About one-half of the patients presented systemic symptoms; all but one showed more than one involved site, mostly an association of nodal and extranodal sites. All patients (1 in stage 1,7 in stage II, and 5 in stage III) were treated with a modified version of the LSA2-L2 protocol. Survival and event-free survival at 4 years were 100% and 62.9%, respectively. Two out of 3 relapsed patients presented a recurrence of disease when they were off-therapy 24 and 36 months after first complete remission. Good response to salvage chemotherapy of all the relapsed patients and the long duration of the second complete remission were a distinctive characteristic of this neoplasm when compared to other histological subtypes. The clinical presentation, the tendency to develop late relapses and to achieve and maintain second remission easily suggest that ALCL is a high grade non-Hodgkin's lymphoma, from the histological point of view, but is similar to Hodgkin's disease from the clinical point of view. This would confirm the hypothesis that Hodgkin's disease and ALCL represent a continuous spectrum of the same disease. © 1993 Wiley-Liss, Inc.

Diamond-Blackfan anemia (DBA) is a congenital red blood cell aplasia. No clear explanation has been given of its defective erythropoiesis, although different humoral or cellular inhibitory factors have been proposed. To clarify the nature of this defect we studied the effect of several human recombinant growth factors on an enriched CD34+ population obtained from the bone marrow of 10 DBA patients. We observed a defect underlying the early erythroid progenitors, which were unresponsive to several growth factors (erythropoietin, interleukin-3 [IL-3], IL-6, granulocyte-macrophage colony-stimulating factor [GM-CSF], erythroid potentiating activity), either alone or in association. The production of cytokines was not impaired, and high levels of IL-3 and GM-CSF were found in phytohemagglutinin-leukocyte- conditioned medium (PHA-LCM) when tested with a sensitive biologic assay on the M-07E cell line. Hematopoietic stem cells in DBA patients may be induced to differentiate to the granulocyte megakaryocyte, but not the erythroid compartment, as shown after CD34+ cell preincubation with IL-3. Addition of the stem cell factor to IL-3 and erythropoietin induces a dramatic in vitro increase in both the number and the size of BFU-E, which also display a normal morphologic terminal differentiation.

Background/Aims: Paediatric primary follicular lymphoma of the testis (PPFLT) is exceptional: the few reported cases seem to lack BCL-2 gene rearrangement and/or protein expression. The aim of this study was to characterise a PPFLT arising in a 4 year old boy. Methods: This case was characterised using conventional histological analysis, immunohistochemistry, and a polymerase chain reaction based method for the detection of immunoglobulin V H chain rearrangements. Results: The neoplasm was staged I E /A; left orchiectomy and chemotherapy were performed, producing complete remission. Histology showed a predominantly follicular lymphoid infiltrate mainly composed of centroblast-like cells. The phenotype was CD20 + , CD79a + , CD10 + , bcl-6 + , B cell specific activating protein + , κ light chain + , CD30 −/+ , interferon regulating factor 4 −/+ , c-myc −/+ , λ light chain − , CD3 − , bcl-2 − , p53 − , cytokeratin − , and placental alkaline phosphatase − . Lymphomatous elements were found within a CD21 + follicular dendritic cell network and 70% were positive for Ki-67/MIB-1. Molecular analysis revealed monoclonal immunoglobulin heavy chain gene rearrangement and BCL-6 mutations, in the absence of BCL-2 major breakpoint and BCL-2 minor cluster region rearrangements, p53 mutations, and death associated protein kinase gene hypermethylation. Conclusions: These findings suggest a different pathogenesis of PPTFL compared with adult follicular lymphoma and might explain its favourable course in spite of aggressive histology.

BACKGROUND In 1991, the Italian Association for Pediatric Hematology-Oncology and the National Council of Research (CNR) initiated an Italian Cooperative Study (SE 91-CNR Protocol) with the main objective of improving the overall survival (SUR) and the event free survival (EFS) of children and young adults with localized Ewing sarcoma and primitive neuroectodermal tumors of bone compared with a previous study (IOR/Ew2 Protocol). METHODS Between November 1991 and November 1997, 165 patients were enrolled in this study, 160 of whom were evaluable. The patients were treated with a multimodal approach characterized by intensified chemotherapy, hyperfractionated and accelerated radiation therapy, and the addition of ifosfamide and etoposide to standard chemotherapy with vincristine, actinomycin-D, doxorubicin, and cyclophosphamide. RESULTS After a median follow-up of 37 months, 126 of the 160 evaluable patients remained free of disease recurrence. Thirty-one patients developed a disease recurrence (20 with disseminated disease). CONCLUSIONS The 3-year SUR and EFS rates found in the current study (83.6% and 77.8%, respectively) may be considered satisfactory. Only age at diagnosis ≤14 years and a good histologic response appeared to affect the outcome of patients with localized Ewing sarcoma positively. These results appear to demonstrate the efficacy of the addition of ifosfamide in induction chemotherapy to four-drug standard combination chemotherapy, as confirmed by the improved outcome in terms of 3-year EFS reported in the SE 91-CNR Protocol compared with the IOR/Ew2 Protocol (77.8% vs. 60.7%). In addition, the better outcome also could be explained by the change in treatment strategy with a trend toward the use of more surgery than radiation therapy compared with the authors' previous protocol. Cancer 1999;86:421–8. © 1999 American Cancer Society.

The hematopoietic defect of Diamond-Blackfan anemia (DBA) results in selective failure of erythropoiesis. Thus far, it is not known whether this defect originates from an intrinsic impediment of hematopoietic progenitors to move forward along the erythroid pathway or to the impaired capacity of the bone marrow (BM) microenvironment to support proliferation and differentiation of hematopoietic cells. Reduced longevity of long-term bone marrow cultures, the most physiologic in vitro system to study the interactions of hematopoietic progenitors and hematopoietic microenvironment, is consistent with a defect of an early hematopoietic progenitor in DBA. However, stromal adherent layers from DBA patients generated in a long-term culture system, the in vitro counterpart of BM microenvironment, did not show evidence of any morphologic, phenotypic, or functional abnormality. Our major finding was an impaired capacity of enriched CD34+ BM cell fraction from DBA patients, cultured in the presence of normal BM stromal cells, to proliferate and differentiate along the erythroid pathway. A similar impairment was observed in some DBA patients along the granulomacrophage pathway. Our result points to an intrinsic defect of a hematopoietic progenitor with bilineage potential that is earlier than previously suspected as a relevant pathogenetic mechanism of the disease. The finding of impaired granulopoiesis in some DBA patients underlines the heterogeneity of this rare disorder.

The role of ifosfamide as first-line chemotherapy treatment of non metastatic Ewing's sarcoma of the extremity is still under discussion. The purpose of this paper is to report the results achieved in a neoadjuvant protocol (REN-3) in which ifosfamide, added to the conventional VACA regimen, was employed since the induction phase. Induction chemotherapy consisted of vincristine, cyclophosphamide, doxorubicin, actinomycin-D and ifosfamide. After local treatment, patients received the drugs used in the induction phase and etoposide. Between November 1991 and November 1994, 61 patients with non metastatic Ewing's sarcoma of the extremity were treated. Forty-nine patients underwent surgery and 73.5% of them had a good histologic response. At a median follow-up of 60 months (range 32-76), 48 patients (79%) remained continuously disease-free. The 5-year event-free and overall survival were 77% and 87%, respectively. These results were significantly better both in terms of histologic response or event-free and overall survival than those obtained in 58 patients with non metastatic Ewing's sarcoma of the extremity treated in a previous protocol (REN-2) in which the same drugs were used, but ifosfamide was employed only in the maintenance phase. The present study suggests the importance of early use of ifosfamide in the treatment of patients with non metastatic Ewing's sarcoma of the extremity.

A multicentric retrospective study on leukemic ophthalmopathy (LO) is reported. It includes 21 patients, 16 males and 5 females, with acute leukemia (AL) observed in 10 SIOP centers. LO developed in three patients at the time of diagnosis of AL; five patients were in first complete remission (three off therapy); four patients were in second or third remission; and nine were in combined relapse. Most frequent symptoms were blurred vision, photophobia, and ocular pain. Two patients with acute nonlymphoblastic leukemia died before treatment; another underwent bone marrow transplantation; one patient with B-cell acute lymphoblastic leukemia (B-ALL) treated with chemotherapy and radiotherapy died 4 months after LO; the remaining 17 children were treated according to different schedules with (10) or without (7) radiotherapy on the affected eye. Twelve patients achieved ocular remission and four of these had a second ocular relapse. Complete remission after LO treatment lasting for more than 3, 7, 24, 29 months was observed in four patients. The authors conclude that cure is possible in patients who had LO in first complete remission treated with chemotherapy and radiotherapy at high dose on the affected eye.

Ten healthy donors and four patients with Diamond-Blackfan anemia (DBA) have been investigated for granulocyte-macrophage colony stimulating factor (GM-CSF) and stem cell factor (SCF) production by bone marrow-enriched fibroblasts (BMEF) in a highly sensitive biological assay on growth factor-dependent M-07e cells. M-07e cells detected active soluble kit-ligand from normal bone marrow fibroblasts as well as from DBA BMEF which produce constitutively significant amounts of SCF. Interleukin 1 beta (IL-1 beta) induced a significant increase of soluble SCF from both normal and DBA BMEF. GM-CSF was undetectable in unstimulated cultures, while its production by bone marrow microenvironmental cells was documented for both normal and DBA patients after IL-1 beta stimulation in vitro.

• Objective. —To determine the effects of 18-Gy cranial irradiation on growth, growth hormone (GH) secretion, and pituitary magnetic resonance imaging in children who underwent previous irradiation for treatment of acute lymphoblastic leukemia. Design. —Clinical survey. Setting. —Department of Pediatrics of the University of Bologna (Italy). Patients. —Ten boys and 18 girls who were treated for acute lymphoblastic leukemia; median age at diagnosis was 3.1 years and at the end of follow-up was 11.5 years. Measurements and Results. —Height was periodically measured from diagnosis until the end of follow-up, when GH secretion study and magnetic resonance imaging were performed. The mean height SD score was significantly lower than at diagnosis only at the end of treatment. Nocturnal mean GH concentration and GH response to pharmacological tests (arginine and levodopa [L-dopa]) were pathological in 22 cases (81.5%) and 18 cases (64.3%), respectively. Sixteen cases (59.2%) had a blunted GH release to the three tests. Mean pituitary anterior lobe height was reduced and seven subjects (25%) showed an empty sella. Conclusions. —Cranial irradiation with 18 Gy does not seem to influence the growth pattern of most children who are treated for acute lymphoblastic leukemia, despite severe impairment of GH secretion and morphological abnormalities of the sellar area. However, a follow-up until final height is necessary. ( AJDC . 1992;146:1343-1348)

Ninety-one children with cancer (thirty-seven with leukemia and fifty-four with solid tumors)--school aged (elementary and middle school), residing in Emilia-Romagna Region (Italy), and receiving treatment at the Department of Pediatrics (III), University of Bologna, from August 1973 to April 1987--took part in a study of school behavior as perceived by the teacher. The research was carried out through a 29-item forced-choice questionnaire based on the questionnaire proposed by Deasy-Spinetta for a similar study in the U.S.A. Results revealed that children with cancer have a school behavior scoring at levels significantly lower than controls. There are more difficulties for children attending middle than elementary school, for children on therapy than off therapy, and for children with leukemia than with solid tumors. In conclusion, the main obstacle to school performance seems to be lower attendance, which is mainly due to treatment and clinic visits and probably in part to an overprotection and an excessive concern on the part of physicians and parents.

Osseous relapse, as distinct from bone marrow relapse, is possible during treatment of childhood leukemia. The authors have observed an isolated leukemic bone lesion in an 8-year-old boy in complete bone marrow remission after a second full course of chemotherapy for a testicular leukemic localization. The radiological signs in our case are peculiar because a small bone of the foot (right talus) showed an increased density instead of rarefaction; histological examination demonstrated leukemic bone infiltration. Local radiotherapy (2400 cGy) was given and multidmg induction and maintenance for one year. Two years after the histological diagnosis the child is still in complete remission. This observation suggests that structural bone may be a sancturay site for leukemic cells.

Four cases of infantile sarcomatous renal tumors are reported. Rhabdomyoblastic differentiation was investigated in these tumors by the immunoperoxidase method using antimyoglobin sera. Rhabdomyoblastic cells were found in 2 cases and in a metastasis of one case in which the primary tumor was composed by undifferentiated cells negative for myoglobin stain. The histogenesis of these neoplasias is discussed, and it is suggested that they are a sarcomatous variant of Wilms’ tumor.

A case of cystic nephroma is described in a 20-month-old female. The diagnosis of this rare renal pathologic lesion is essentially based on its pathologic features. The treatment consisted of nephrectomy followed by a brief course of chemotherapy. The literature is reviewed with regard to the pathologic features and treatment of this lesion, which has a favorable prognosis.

Summary Serum samples were examined from 125 children (1–12 years) entering a paediatric unit for haematological disorders (74: acute lymphoblastic leukaemia; 11: Hodgkin's disease; 17: solid tumors; 23: non neoplastic disorders). Fifty healthy children were also studied. The sera were tested for class specific IgG and IgM antibodies to EB viral capsid antigen (VCA) and early antigen (EA), and for heterophil antibody. Serological findings consistent with a recent EBV primary infection, not related to the onset of the diseases, were found in six per cent of the patients. Antibodies against EBV-VCA were found in a significantly ( P

From June 1976 to May 1980, 25 previously untreated children with non-Hodgkin's lymphoma (NHL) were studied and treated with a protocol modified from the one (LSA2L2) proposed by Wollner [8]. Stage III and IV had, in addition, prophylactic treatment of the central nervous system (CNS) with cranial irradiation (2,400 rad plus intrathecal metho-trexate). The complete remission rate is 96%. Of these patients, 76% are disease free surviving after a median observation time of nearly two years. The disease-free actuarial survival is 100% for 6 children with Stage I-II disease and 68% for 19 Stage III-IV children after median observation times respectively of 25 + and 19 + months. None of the 19 high-risk patients developed CNS disease after prophylactic treatment. Mediastinal involvement and leukemic conversion at diagnosis were not unfavorable prognostic factors, but primary skeletal or subcutaneous disease and Burkitt-type histology were ominous features in patients treated by this regimen. It is concluded that good results are obtained when an aggressive multimodal and multiple drug regimen like the LSA2-L2 is coupled with CNS prophylaxis and is used assiduously to maintain complete remission during the first 12 months of treatment.

• To evaluate the effects of two different doses of cranial irradiation on growth and growth hormone (GH) release, we studied 61 children with acute lymphocytic leukemia who had survived at least five years in continuous complete remission. Forty-three children received 24 Gy (group 1) and 18 children received 18 Gy (group 2). Height was evaluated at diagnosis, at the end of treatment, and 6, 12, and 24 months later. Growth hormone release was evaluated by arginine and levodopa tests after the end of treatment. After diagnosis, the height SD score decreased significantly in both groups; two years after the end of treatment, only group 1 showed an SD score for height that was still significantly lower than at diagnosis. Group 1 showed impaired GH responses to the tests and, compared with controls, group 1 in fact included a percentage of subjects with a normal response to levodopa (ie, >8 μg/L) that was significantly lower (56.4% vs 83.3%) and a percentage of nonresponders to both tests that was significantly higher (21.6% vs 0%). These data indicate that only patients treated with lower cranial irradiation dosage (18 Gy) had complete growth recovery and normal GH responses to pharmacologic tests. ( AJDC 1988;142:1199-1202)

The clinical features of 30 children with IV-S neuroblastoma have been reviewed. They were treated at 11 Italian pediatric institutions in the period 1970-1981. Patients with IV-S neuroblastoma comprise 6.1% of all the neuroblastoma cases observed during that period. The age at diagnosis ranged from birth to 11 months (mean, 3 months). The distribution of "primary" lesions was of interest. The adrenal gland was affected most often (57% of patients), but tumors of the chest and neck were also encountered. No specific "primary" lesion was identified in ten children. The most frequent site of widespread disease was the liver (87%). Neither the size of the "primary" tumor, nor the number or size of subcutaneous nodules was of prognostic significance. Unfavorable features were age less than 2 months and clinical signs of pulmonary, renal, or hepatic embarrassment. These data confirm the need for prompt intervention in the infant who is suffering from compression of these vital structures by the enlarged liver. Radiation therapy is to be preferred for this purpose, because of the often severe toxicity that is associated with chemotherapy in infants. One, and possibly two babies in this series died of chemotherapy-related complications.

Hereditary neuroblastoma in a pair of identical twins is reported. In one of the twins the tumor occurred in fetal life and caused death of the twin before birth; in the other one, the tumor occurred at two months of life as IV-S neuroblastoma in the liver with primary tumor undetected. The unusual clinical course of the latter case is described: twice there was tumor regression, but in spite of treatment, fatal uncontrolled growth occurred. The family history, characterized by neoplasms of dissimilar cell types but without additional cases of neuroblastoma, is also detailed.

From June 1976 to December 1984, 48 previously untreated children with non-Hodgkin's lymphoma (NHL) were treated according to the LSA2-L2 protocol, modified by inclusion of cranial irradiation for patients in stage III and stage IV disease. According to the staging system proposed by Wollner, 4 patients were in stage I, 8 in stage II, 11 in stage III, 8 in stage IVA (less than or equal to 25% blasts in the bone marrow), 15 in stage IVB (greater than 25% blasts in the bone marrow), and 2 in stage IV central nervous system disease. The complete remission rate was 95.8%. The relapse-free survival (RFS) rate of 46 complete responders was 76% after a median observation time of 47+ months. Only 1 of 35 high-risk responder patients developed CNS relapse after prophylactic treatment. Clinical stages were related to the RFS: 100% in stage I-II vs. 69% in stage III-IV. All 8 patients in stage IV were alive without evidence of disease with a median observation time of 59+ months. Fifteen patients in stage IVB who had leukemia-lymphoma syndrome attained 59% RFS with a median observation time of 39+ months. After a median observation time of 38+ months, 29 of 37 patients are off therapy. The results emphasize the value of both the histologic and immunologic features and the stage of disease in predicting the outcome of NHL in children. The LSA2-L2 regimen appears to be a very effective protocol for children with lymphoblastic lymphoma, although it may be less efficacious for patients with large bone marrow involvement.

We evaluated the long-term results obtained in 402 patients with non-metastatic Ewing's sarcoma (ES) of the bone treated in a single institution with adjuvant and neoadjuvant chemotherapies between 1972 and 1992. Multivariate analyses showed male gender, age older than 14 years, high serum lactate dehydrogenase (LDH) level, axial location of the tumour, use of radiotherapy alone as a local treatment, and poor histological response to chemotherapy, to be independent, adverse prognostic factors for event-free survival (EFS). At a mean follow-up of about 18 years (10-30 years), 177 patients (44.0%) remained continuously free of disease, 2 died of doxorubicin-induced cardiotoxicity and 8 developed a second neoplasm (5 died, and 3 are alive and free of disease). 215 patients relapsed with metastases and/or local recurrence: 14 are alive and free of disease, 1 is alive with uncontrolled disease, and 200 died. The overall survival (OS) at real follow-ups of 5-, 10-, 15- and 20-years was 57.2, 49.3, 44.9 and 38.4%, respectively. We conclude that since local or systemic relapses, treatment-complications and second malignancies are more common after 5 years or more from the beginning of treatment; a long-term follow-up is mandatory for patients with ES. © 2003 Elsevier Ltd. All rights reserved.

SummaryHereditary thrombocytopenias represent heterogeneous clinical and genetic syndromes. They include a consistent group of families which are considered as a separate clinical entity, characterized by autosomal dominant transmission, incomplete penetrance in females, chronic thrombocytopenia with early age of onset and frequently increased platelet volume, without any other hematologic abnormality. The molecular defect in these families is still unknown. We describe 2 families in 3 generations (10 patients), and report the first study of the TPO/ c-mpl system in autosomal dominant thrombocytopenia. We performed mutational screening of c-mpl coding, flanking introns and promoter regions in 2 probands from the two families by DNA sequencing. The results do not provide evidence of c-mpl sequence alterations in either of the 2 families investigated. Moreover, the normal TPO serum levels detected in 5 patients from each family leads us to exclude the possibility of a defect in TPO production in our families. Finally, the involvement of both c-mpl and TPO genes in the pathogenesis of thrombocytopenia in these two families was excluded by negative results of linkage analysis.

The results of discontinuing therapy in children with acute lymphocytic leukemia observed at four associated institutions are presented. Of the 247 patients who achieved complete remission, 122 (49.3%) reached the point of discontinuing therapy after 2-4 years of continuous remission. The median period off therapy was 13 months with a range of 1-69 months. Of the 122 children removed from therapy, 27 (22.1%) relapsed, mainly in the bone marrow; relapses occurred 1-32 months after cessation of therapy (median ten months) with only two relapses occurring later than two years. By actuarial analysis, 57% of the patients are projected in continuous remission after five years from cessation of therapy. Neither selected features at diagnosis nor single modalities of treatment were found to predict whether relapse would occur after discontinuing therapy. Long-term remission and possibly cure can be expected in over one-third of newly diagnosed children with ALL after 2-4 years of antileukemic treatment.

PURPOSE This study was performed to assess the prognostic value of the proposed histopathologic method to evaluate the response of the primary tumor to preoperative chemotherapy in Ewing's sarcoma. PATIENTS AND METHODS The response to chemotherapy was evaluated from the specimens of 118 Ewing's sarcoma patients, who were preoperatively treated by chemotherapy alone. Responses were graded I to III (macroscopic viable tumor, microscopic viable tumor, and no viable tumor cells, respectively). Follow-up data were available for all patients, with a mean follow-up duration of 86 months (range, 30 to 158). RESULTS A statistically highly significant difference was observed in outcome among the three groups of patients. For patients with total necrosis (grade III response), the estimated 5-year disease-free survival rate was 95%, in contrast to 68% for grade II responders and 34% for grade III responders (P < .0001). This difference was also confirmed when any single group was compared with the other groups. Among the parameters tested, patient age and the size of tumor had some prognostic value. CONCLUSION The proposed histopathologic grading, to evaluate the effect of chemotherapy on the primary tumor, had the strongest correlation to clinical outcome. This method could therefore be used to identify patients with a high risk of recurrent disease. These patients could be randomized to receive alternative postoperative treatments to investigate whether more aggressive therapies will improve outcome.