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Background: Etoposide, an inhibitor of the normal religation activity of the nuclear enzyme topoisomerase II, can induce a secondary acute myeloid leukemia characterized by site-specific DNA rearrangements. The schedule of drug administration appears to be a clinical risk factor for this devastating treatment complication.Purpose: We tested the hypothesis that prolonged exposure of leukemia cells in vitro to low concentrations of etoposide, compared with short exposures to high concentrations, could produce equivalent or greater desired cytotoxic effects, with decreased occurrence of undesired site-specific double-stranded DNA recombinational events (i.e., recombinogenesis).Methods: We used the frequency of V(D)J (variable-diversity-joining) recombinase-mediated deletions of exons 2 and 3 of the hypoxanthine phosphoribosyltransferase (HPRT) gene as a biomarker of etoposide-induced, nonhomologous, site-specific DNA rearrangement. A polymerase chain reaction-based technique was used to measure exon 2 + 3 deletions in human lymphoid leukemia CCRF-CEM cells 6 days after either 4-hour or 24-hour treatment with etoposide at clinically relevant concentrations. Cytotoxic effects of etoposide (determined by the number of viable cells present in the treated compared with the control [i.e., untreated] cells) were measured 6 days after treatment of the cells. The frequency of the exon 2 + 3 deletion following the two treatment-duration conditions was compared by use of the Mantel-Haenszel statistic. All P values resulted from two-sided tests.Results: Cytotoxicity increased with increasing etoposide concentration and exposure duration, as expected. By day 6, the frequency of exon 2 + 3 deletions was significantly higher (global P value = .0003) after the 4-hour treatment than after the 24-hour treatment, regardless of whether the frequency was assessed at etoposide concentrations achieving equivalent (e.g., 95%) cytotoxicity (14.2 x 10(-7) versus 4.1 x 10(-7) or at equivalent etoposide concentrations (e.g., 1 microM) (10.8 x 10(-7) versus 1.3 x 10(-7). Thus, the ratio of desired cytotoxic to undesired recombinogenic effects was higher with the 24-hour schedule. After the treated cells were subcloned at limiting dilutions, the frequency of the exon 2 + 3 deletion increased from 16.3 x 10(-7) to 4.33 x 10(-3), indicating that the recombinational event is not necessarily lethal.Conclusion: For all drug concentrations and levels of cytotoxicity studied in CCRF-CEM cells, there was a greater ratio of cytotoxicity to genetic recombination following prolonged exposure to etoposide than following brief exposure.Implication: These data suggest that recombinogenesis is not inextricably linked to cytotoxicity. If confirmed in the clinical setting, the use of prolonged dosage schedules may provide a means to decrease the risk of etoposide-induced acute myeloid leukemia without compromising treatment efficacy. [ABSTRACT FROM AUTHOR]

Ion beam bombardment is a powerful technique to improve the surface properties of polymeric materials without changing the bulk properties. Herein, Makrofol LT films were bombarded with low energy of oxygen ions at different fluences ranging from 11 × 10 17 to 44 × 10 17 ions/cm 2 . X-ray diffraction, FTIR spectroscopy, surface-roughness tester, ultraviolet-visible spectroscopy, and Fluorescence spectroscopy were used to examine the change in the structure, chemical functional groups, alteration in surface roughness parameters, and photo-physical properties. The obtained results evidenced that the ordering and disordering structure of bombarded Makrofol LT films were influenced by ion beam irradiation according to the ion fluence. The FTIR spectroscopy of functional group examination revealed the possibility of the presence of sp 2 -carbon clusterization and amorphization. The surface roughness parameters increase as the ion fluences increase. Optical measurements exhibit a shift of absorption-edge towards the visible zone that correlated to the surface damage and the creation of CC bonds. The fluorescence spectra exhibit that the yield intensities decrease with increasing ion fluences. This refers to improvement in the radiative-recombination rate relative to non-radiative recombination. This is attributable to the growth of clusters, the increase of density states of the surface, and the increase in the surface roughness of the bombarded samples., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Lung cancer (LC) is the most common cancer-related death globally, and many efforts have been made to improve the patient care of LC patients, as well as the development of efficient methods and a wider range of biomarkers for prognosis, diagnosis, and treatment purposes. MicroRNAs (miRs, miRNAs) regulate a wide range of cellular functions and play a key role in the development and spreading of LC by inhibiting or degrading the expression of their target protein-coding genes. Because of their dysregulation and disruption in function, miRNAs have been linked to the malignant pathophysiology of LC by influencing many cellular functions involved in the disease. These biological processes include increased invasive and proliferative potential, cell cycle abnormality, apoptosis evasion, promotion of angiogenesis, EMT and metastasis, and reduced susceptibility to certain treatments. Here, we discuss the findings from recent years that show the role of oncogenic and TS miRNAs in LC, as well as their significance in LC pathogenesis, and resistance to anticancer therapy. We also explore the biological relevance of miRNAs and their clinical application in LC diagnosis and prognosis., Competing Interests: Declaration of Competing Interest The authors declare they have no conflict of interest., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

Background and Aims: The level of albuminuria is used to evaluate diabetic nephropathy (DN). However, to detect or predict the early stages of DN, better biomarkers are needed., Methods: This study is a case-control observational study. 80 Egyptians participated in the study: 60 patients with type 2 diabetes mellitus (T2DM) were divided into three groups (20 patients each), and 20 healthy subjects with matched age and gender were used as controls. Demographic and laboratory data were analyzed. An enzyme-linked immunosorbent assay was used to determine the levels of four biomarkers of DN; urinary adiponectin (ADP), urinary transferrin, serum Zinc Alpha 2 Glycoprotein (ZAG), and urinary Retinol Binding Protein (RBP)., Results: The levels of DN biomarkers urinary ADP, transferrin, RBP, and serum, ZAG were significantly higher in patients with T2DM than in controls. The ROC curve of the validity of the simultaneous use of all four biomarkers in predicting albuminuria indicates a sensitivity of 90% and a specificity of 90%. The Area Under the Curve (AUC) was 0.948, the 95% confidence interval was 0.998-0.897, and the p-value was 0.001., Conclusions: In patients with T2DM, urine adiponectin, transferrin, RBP, and serum ZAG concentration may be useful biomarkers in the early diagnosis of DN. A further longitudinal prospective study is required to explore the potential utility of these biomarkers., Competing Interests: Declaration of competing interest The authors of these paper certify that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript., (Copyright © 2022 Diabetes India. Published by Elsevier Ltd. All rights reserved.)

The brain is the most essential part of the central nervous system which regulates and coordinates all body activities. Based on its phylogenetic development from the neural tube, the brain is divided into rhombencephalon (hindbrain), mesencephalon (midbrain) and prosencephalon (forebrain). The present study is achieved to describe the morphological characteristics of the normal forebrain in the donkey using the matched magnetic resonance imaging (MRI) and cross-sectional anatomy. Ten cadaveric heads of healthy adult donkeys of both sexes were used. Two heads were examined using a 1.5 Tesla MRI scanner, and the brains of the other heads were gently extracted; six brains were sectioned into transverse, dorsal and sagittal slices, and two brains were grossly inspected. MR images were selected in correlation to their closely corresponding gross sections. Both cross-sectional anatomy and MRI scans showed extensive gyration of the neocortex. The forebrain structures appeared with variable intensities on three sequences, Flair, T1-weighted and T2-weighted MRI, enabling comprehensive evaluation of the relevant neuroanatomical structures. The present study provided a precise neuroanatomical atlas of the forebrain in the donkey which could help in the quick and efficient interpretation of clinical diseases of the forebrain, localization of the forebrain functions and evolutionary neurobiology., (© 2021 Wiley-VCH GmbH.)

The paper deals with the structure, morphology and magnetic properties of two different iron concentrations (20 and 33 mol.%) of Fe2O3-SiO2 nanocomposites, prepared by sol-gel technique and exposed to different gamma-irradiation doses (0, 30 and 60 kGy). The nanocomposites were investigated through XRD, TEM, SEM, FTIR and EPR measurements. Superparamagnetic iron (III) oxide nanoparticles with a narrow size distribution, dispersed over the amorphous silica matrix, are assumed to be present in all the samples before and after irradiation. Before irradiation, a lot of γ-Fe2O3 crystalline ferromagnetic nanoparticles are assumed to be formed particularly for sample containing 33 mol.% Fe2O3, while exposing the samples to irradiation results in the transformation of γ- to α-Fe2O3. Iron concentrations and/or irradiation of the samples are assumed to cause changes in the bond angles and/or bond lengths of the structural silicate units within network, as well, the increase of more defect centers induced by irradiation as evident through the variations of the IR bands intensity. The EPR results show both intensity and line width increase with increasing Fe2O3 concentration. The EPR signals for the samples consist of a well defined symmetrical broad signal at g≈2.0 ascribed to antiferromagnetic interactions between the Fe(2+) and Fe(3+) clusters. Condensed clusters of Fe(3+) ions are observed to give rise to a resonance line at g∼2 whose position and width do not depend on the Fe2O3 concentrations. The EPR signal intensity is observed to be significantly decreased in the sample 33 mol.% or stabilized in the sample 20 mol.% by γ-irradiation. This reflects simultaneous spin transformation from the high-spin state of Fe III to the low-spin state of Fe II. As a final point, an effort has been given to found the possibility to use one of these studied nanocomposite materials as candidate for radiation shielding purposes., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Malignant fibrous histiocytoma (MFH) is a controversial entity. In the current study, the authors reviewed their institutional experience with these tumors to characterize their clinical features in pediatric patients and assess the impact of surgical resection on outcome., Methods: The records of the 28 patients who were diagnosed with MFH or MFH variants of soft tissue between January 1971 and December 2000 were reviewed and the tumors were reclassified according to the World Health Organization guidelines., Results: Seventeen patients had MFH; 10 patients had angiomatoid fibrous histiocytoma (FH), and 1 patient had a plexiform fibrohistiocytic tumor. The median age of patients at the time of diagnosis was 7.3 years. The most common primary tumor site was the extremity (n = 14). Metastatic disease (to the lung) was present in only three patients, each of whom had MFH. Of the 17 MFH tumors, 13 were high grade, 8 were invasive, and 6 measured > 5 cm. All angiomatoid FH tumors and the plexiform fibrohistiocytic tumor were noninvasive, and 10 measured < or = 5 cm. Surgical treatment was comprised of wide local excision with clear margins (n = 18), amputation (n = 3), excision with positive or indeterminate surgical margins (n = 4), partial resection (n = 2), or biopsy only (n = 1). Primary reexcision was performed for 21 patients. The 5-year survival and event-free survival (EFS) estimates for patients with MFH were 76.5% +/- 11.2% and 70.6% +/- 12.1%, respectively; the 5-year survival and EFS estimates were 100% +/- 0% for patients with angiomatoid FH or plexiform fibrohistiocytic tumor. Compared with partial resection or excision, wide local excision or amputation was found to have a positive impact on the probability of EFS in patients with localized disease (P = 0.008). All four patients with metastatic or unresectable MFH had died by the time of last follow-up., Conclusions: MFH should be distinguished from angiomatoid FH and plexiform fibrohistiocytic tumors, both of which are less aggressive. Wide local excision is the treatment of choice, regardless of the histology or grade of the tumor. Patients with metastatic or unresectable MFH appear to have a poor outcome and would benefit from more effective therapies., (Copyright 2003 American Cancer Society.)

Purpose: To study the pharmacokinetics and pharmacodynamics of once- versus twice-daily oral etoposide in children with relapsed or refractory acute lymphoblastic leukemia (ALL)., Patients and Methods: Fifty-eight patients were randomly assigned to etoposide at 50 mg/m(2)/d with once- versus twice-daily doses for 22 days. On day 8, vincristine, asparaginase, and dexamethasone were started. Etoposide pharmacokinetics and pharmacodynamics were studied for 47, 28, and 26 patients on day 1, 8, and 22, respectively, of remission reinduction therapy., Results: Of 48 patients with pharmacokinetic data, 42 (87.5%) achieved complete remission, three (6.3%) failed to achieve remission, and three (6.3%) died during induction. Median etoposide day 8 area under concentration-time curve (AUC) and cumulative AUC tended to be greater (P =.06 and P =.07, respectively) in patients (n = 23) who achieved complete remission (24 and 522 micro mol/L x h, respectively) than in patients (n = 3) who did not (14 and 303 micro mol/L x h, respectively). Three of eight patients with plasma concentrations exceeding 1.7 micro M (1 micro g/mL) for more than 8 hours daily, compared with one of 20 patients with concentrations exceeding 1.7 micro M for

Purpose: To improve the control of hyperuricemia in patients with leukemia or lymphoma, we tested a newly developed uricolytic agent, recombinant urate oxidase (SR29142; Rasburicase; Sanofi-Synthelabo, Inc, Paris, France), which catalyzes the oxidation of uric acid to allantoin, a highly water-soluble metabolite readily excreted by the kidneys., Patients and Methods: We administered Rasburicase intravenously, at 0.15 or 0.20 mg/kg, for 5 to 7 consecutive days to 131 children, adolescents, and young adults with newly diagnosed leukemia or lymphoma, who either presented with abnormally high plasma uric acid concentrations or had large tumor cell burdens. Blood levels of uric acid, creatinine, phosphorus, and potassium were measured daily. The pharmacokinetics of Rasburicase, the urinary excretion rate of allantoin, and antibodies to Rasburicase were also studied., Results: At either dosage, the recombinant enzyme produced a rapid and sharp decrease in plasma uric acid concentrations in all patients. The median level decreased by 4 hours after treatment, from 9.7 to 1 mg/dL (P =.0001), in the 65 patients who presented with hyperuricemia, and from 4.3 to 0.5 mg/dL (P =.0001) in the remaining 66 patients. Despite cytoreductive chemotherapy, plasma uric acid concentrations remained low throughout the treatment (daily median level, 0.5 mg/dL). The urinary excretion rate of allantoin increased during Rasburicase treatment, peaking on day 3. Serum phosphorus concentrations did not change significantly during the first 3 days of treatment, decreased significantly by day 4 in patients presenting with hyperuricemia (P =.0003), and fell within the normal range in all patients by 48 hours after treatment. Serum creatinine levels decreased significantly after 1 day of treatment in patients with or without hyperuricemia at diagnosis (P =.0003 and P =.02, respectively) and returned to normal range in all patients by day 6 of treatment. Toxicity was negligible, and none of the patients required dialysis. The mean plasma half-lives of the agent were 16.0 +/- 6.3 (SD) hours and 21.1 +/- 12.0 hours, respectively, in patients treated at dosages of 0.15 or 0.20 mg/kg. Seventeen of the 121 assessable patients developed antibodies to the enzyme., Conclusion: Rasburicase is safe and highly effective for the prophylaxis or treatment of hyperuricemia in patients with leukemia or lymphoma.

Purpose: To determine the activity of carboplatin/ifosfamide in patients with previously untreated osteosarcoma and to estimate patient outcomes after a multiagent chemotherapy protocol that eliminated cisplatin., Patients and Methods: Sixty-nine patients with newly diagnosed, previously untreated osteosarcoma received three cycles of carboplatin (560 mg/m(2) x 1) and ifosfamide (2.65 g/m(2)/d x 3). Assessment of response was evaluated after two (week 6) and three (week 9) chemotherapy cycles. At week 9, histologic response was assessed. Adjuvant therapy comprised two additional carboplatin/ifosfamide cycles, doxorubicin, and high-dose methotrexate. Patients were stratified at enrollment: stratum A, resectable primary tumor without metastases; stratum B, unresectable primary tumor; and stratum C, metastatic disease at diagnosis. Week 6 response was compared with that of a historic group that received only ifosfamide during the initial window evaluation., Results: The clinical and radiographic response rate to three cycles of carboplatin/ifosfamide was 67.7% (95% confidence interval, 55.0% to 78.8%). Compared with the historic population who received only ifosfamide, the combination of carboplatin and ifosfamide reduced the progressive disease rate at week 6 (31.9% v 9%, P: = .003). For patients in stratum A, the 3-year event-free survival and survival were 72.3% +/- 6.7% and 76.4% +/- 6.4%, respectively. Patients who received carboplatin-based therapy had less long-term renal toxicity and ototoxicity., Conclusion: This pilot trial suggests that carboplatin/ifosfamide combination chemotherapy has substantial antitumor activity. In the context of a multiagent chemotherapy protocol comprising high-dose methotrexate and doxorubicin, we found that the addition of carboplatin/ifosfamide resulted in patient outcomes comparable to trials using cisplatin-based therapy with less long-term toxicity.

Background: Bone sarcomas of the head and neck are difficult to resect. The authors reviewed their institutional experience with these tumors to characterize patients' clinical findings and to assess the impact of surgical resection on outcome., Methods: The records of the 28 patients with bone sarcomas originating in the head and neck treated at St. Jude Children's Research Hospital between March 1962 and January 1998 were reviewed., Results: There were 10 males and 18 females (median age, 12.6 years) each with a single sarcoma: osteosarcoma (18), Ewing sarcoma (7), malignant fibrous histiocytoma (MFH) (2), and fibrosarcoma (1). Primary tumor sites included the maxilla (13), skull (10), mandible (2), and other sites (3). All but one patient with Ewing sarcoma had localized disease at the time of diagnosis. All patients underwent surgery: complete resection, 8; gross total resection, 4; incomplete resection, 14; and biopsy only, 2; 22 also received chemotherapy. Radiotherapy was given to all patients with Ewing sarcoma and to four patients with primary osteosarcoma. Twelve patients survived a median of 8.4 years after diagnosis, 14 died of disease, and 2 died of unrelated causes. Local disease progression was evident in 12 patients (9 with osteosarcoma, 2 with MFH, and 1 with Ewing sarcoma) who died of disease, 9 of whom had the initial treatment of biopsy alone or incomplete resection. Patients with osteosarcoma who had the initial treatment of incomplete resection or biopsy alone were more likely to experience local failure (P = 0.001) and had poorer survival (P = 0.014) than those who underwent complete or gross total resection., Conclusions: Bone sarcomas of the head and neck are rare among children and most often are localized at the time of diagnosis. Incomplete resection of osteosarcoma is associated with local failure and poor outcome. Although aggressive surgery is essential for the cure of osteosarcoma, its necessity in the treatment of Ewing sarcomas remains controversial.

Purpose: We analyzed the clinical features and outcome of patients with radiation-associated osteosarcoma treated during the era of contemporary chemotherapy., Patients and Methods: The characteristics and outcome of 23 patients (17 males and six females) treated during childhood or adolescence for a solid tumor who later developed osteosarcomas within the radiation field between 1981 and 1996 were reviewed., Results: The median dose of radiation delivered to the first cancer was 47 Gy. Nineteen patients also received chemotherapy. The median time between radiotherapy and the diagnosis of secondary osteosarcoma was 8 years. Histologic slide review showed conventional central osteosarcoma with various differentiation patterns in 21 cases, together with one case of high-grade surface osteosarcoma and one of periosteal osteosarcoma. The sites of involvement were the craniofacial bones in six cases, the first cervical vertebra in one, the girdle bones in seven, and the extremities of long bones in nine. Three patients had metastatic disease at the diagnosis of osteosarcoma. Palliative therapy was administered to seven patients. The aim of treatment was curative for 16 patients, two of whom underwent amputation without further therapy. Intensive chemotherapy regimens were administered to 14 patients before and/or after surgery. Fifteen patients achieved complete surgical remission. Twelve patients were alive and disease-free at a median follow-up duration of 7.5 years. Overall and event-free survivals at 8 years were 50% and 41%, respectively., Conclusion: Patients with radiation-related osteosarcoma and resectable lesions can be cured with surgery and intensive preoperative and postoperative chemotherapy.

Central nervous system (CNS) relapse has been an obstacle to uniformly successful treatment of childhood acute lymphoblastic leukemia (ALL) for many years. We therefore intensified intrathecal chemotherapy (simultaneously administered methotrexate, hydrocortisone, and cytarabine) for 165 consecutive children with newly diagnosed ALL enrolled in Total Therapy Study XIIIA from December 1991 to August 1994. The 64 patients (39%) who had 1 or more blast cells in cytocentrifuged preparations of cerebrospinal fluid at diagnosis, with or without associated higher-risk features, received additional doses of intrathecal chemotherapy during remission induction and the first year of continuation treatment. Patients with higher-risk leukemia, regardless of cerebrospinal fluid findings, also received additional doses of intrathecal chemotherapy during the first year of continuation treatment. Cranial irradiation was reserved for patients with higher-risk leukemia (22% of the total). The 5-year cumulative risk of an isolated CNS relapse among all 165 patients was 1.2% (95% confidence interval, 0% to 2.9%), whereas that of any CNS relapse was 3.2% (0. 4% to 6.0%). The probability of surviving for 5 years without an adverse event of any type was 80.2% +/- 9.2% (SE). Our results suggest that early intensification of intrathecal chemotherapy will reduce the risk of CNS relapse to a very low level in children with ALL, securing a higher event-free survival rate overall.

Background: The impact of overt testicular disease on survival was assessed among patients treated at the study institution for childhood acute lymphoblastic leukemia (ALL) over a 15-year period. To the authors' knowledge, the frequency of overt testicular involvement at diagnosis of ALL and its impact on treatment outcome have not been reported previously., Methods: The medical records of all 651 boys with ALL enrolled on St. Jude Total Therapy Studies X-XIIIA (May 1979 to December 1993) were reviewed to determine the frequency of overt testicular involvement at diagnosis. The log rank test and sequential Cox regression analyses, adjusted for known adverse features, were used to compare event free and overall survival for patients with and without testicular leukemia. A matched-pairs analysis was then conducted for both outcome measures., Results: Thirteen of the 651 male patients (1.9%) presented with overt testicular leukemia. Compared with the other patients, these 13 boys had a significantly higher frequency of infant or adolescent age at diagnosis, hyperleukocytosis, splenomegaly, and mediastinal mass; a poorer 5-year event free survival (38% [95% confidence interval (CI), 15.4-61.4%] vs. 58% [95% CI, 53.6-61.7%], P = 0.06, log rank test); and a significantly poorer 5-year overall survival (37% [95% CI, 14-60.4%] vs. 75% [95% CI, 71.3-78.4%], P = 0.002). The difference in overall, but not event free, survival was supported by sequential Cox regression analyses and by the matched-pairs analysis (P = 0.04)., Conclusions: Overt testicular involvement with leukemia at diagnosis was associated with an adverse survival in boys with ALL. Testicular irradiation may not be necessary in those patients who present with overt testicular involvement. This finding merits prospective evaluation in a larger sample of similarly treated patients.

Purpose: Although epipodophyllotoxins are commonly used in contemporary treatment regimens for acute lymphoblastic leukemia (ALL), their potential role in CNS-directed therapy has received little attention. We prospectively studied 20 children during initial remission of ALL and 16 children at relapse to assess CSF penetration of etoposide., Methods: Simultaneous plasma and CSF concentrations were assessed at a median of 2.8 hours (range, 0.4 to 5.3) after an intravenous (i.v.) or oral dose in 41 paired samples., Results: Etoposide given at 300 mg/m2 i.v. to patients during first remission and at 50 or 25 mg/m2 orally to those in relapse resulted in median CSF levels of 0.175 mumol/L (range, .066 to 2.12), 0.011 mumol/L (range, .004 to .032), and 0.007 mumol/L (range, .003 to .014), respectively. The CSF etoposide concentration was > or = 10 nmol/L in 20 of 20, five of 10, and two of 11 courses following 300 mg/m2 i.v., 50 mg/m2 orally, and 25 mg/m2 orally, respectively, and was positively related to both the concurrent etoposide plasma concentration (R2 = .64) and to dose (R2 = .73). The median ratio of CSF to plasma concentration was 0.30% (range, 0.09% to 3.12%), which was not related to dose, plasma concentration, or time postdose at which samples were obtained, but was positively correlated with the CSF protein concentration (R2 = 0.43, P = .006). Both the absolute etoposide CSF concentrations (P = .008) and the ratio of CSF to plasma concentrations (P = .023) were higher among first-remission patients who had CSF leukemic blasts at diagnosis compared with those without CSF blasts., Conclusion: Because etoposide concentrations as low as 10 nmol/L may be cytotoxic in vitro, prolonged daily oral low-dose (50 mg/m2) or conventional i.v. doses of etoposide may contribute to successful CNS-directed therapy in children with ALL.

To define better the risk of epipodophyllotoxin-related acute myeloid leukemia (AML) after extended follow-up and to assess responses to intensive salvage therapy, all patients who developed this complication after treatment for acute lymphoblastic leukemia (ALL) or non-Hodgkin lymphoma (NHL) in consecutive clinical trials at St Jude Children's Research Hospital from 1979 to 1994 were studied. Cases with 'lineage switch' or 'clonal selection' were excluded. Epipodophyllotoxin-related AML developed in 32 of 1140 patients treated for ALL and in three of 332 treated for NHL; it was a first adverse event in 25 and two cases, respectively. The complication was diagnosed at 12-130 months (median 34 months) after the initiation of treatment with epipodophyllotoxins; all but one of the cases occurred within 73 months, indicating that the risk is negligible after 6 years. The predominant karyotypic feature was 11q23 translocations (71% of cases); 21q22 rearrangements were rare. In a stepwise Cox regression analysis, two factors increased the risk of this complication: weekly or twice weekly administration of epipodophyllotoxins (P < 0.001); and the administration of asparaginase immediately before epipodophyllotoxin therapy (P < 0.001). Initial responses to salvage therapy were comparable to those reported for de novo AML: 92% of the evaluable patients entered complete remission after combination treatment. Single-agent therapy with 2-chlorodeoxyadenosine induced complete or partial remissions in one-half of the patients treated. The long-term survival rate was dismal. Of the 17 evaluable patients treated exclusively with chemotherapy, only one is alive at 84 months, compared to three of 16 patients who underwent bone marrow transplantation (alive at 10, 23 and 73 months). Cases of epipodophyllotoxin-related AML constitute a unique clinical syndrome that will require innovative strategies for cure.

The risk for induction of epipodophyllotoxin-related acute myeloid leukemia (AML) depends largely on the schedule of drug administration and, to a lesser degree, the cumulative dose. Concomitant use of other genotoxic drugs, such as alkylating agents and cisplatin, can increase the hazard further. We have treated 154 consecutive higher-risk cases of acute lymphoblastic leukemia in our recent Total Therapy Study XIII with an intensive post-remission regimen of chemotherapy that included etoposide given every other week or less often-a schedule associated with a relatively low cumulative incidence of secondary AML in our Study XI. Unexpectedly, four patients have developed secondary AML at 12 to 23 months from the start of treatment (median, 16 months). The 2-year cumulative risk estimate significantly exceeds that for 185 historical controls in Study XI whose continuation regimen included epipodophyllotoxins every other week: 5.4% (95% confidence interval, 0-11%) compared with 1.1% (0-2.6%), P = 0.046. Compared to patients treated in Study XI, those enrolled in Study XIII receive fewer scheduled doses of epipodophyllotoxin (48 (all etoposide) vs 63 (30 etoposide, 33 teniposide)) but 16 to 19 additional doses of L-asparaginase and eight additional doses of high-dose methotrexate, all within the week preceding etoposide treatment. We attribute the apparently increased rate of secondary AML in Study XIII to the use of L-asparaginase immediately before etoposide administration. On this schedule, the enzyme could increase systemic exposure to etoposide or its catechol metabolites and reduce the ability of cells to repair DNA damage.

We have identified a distinctive malignant soft tissue neoplasm that occurred in the head and neck region of six children. Histologically, these neoplasms presented an array of features ranging from low-grade spindle cell to high-grade fibrohistiocytic histologies and often had myoid characteristics. Ultrastructural and immunohistochemical studies indicated that they contained neoplastic myofibroblasts that were variably positive for vimentin (4 positive/4 tested), alpha-smooth muscle actin (4/5), muscle-specific actin (5/5), desmin (2/5), and v-src protein substrate p80/85 (4/5). Three patients died of rapidly progressive unresectable local disease, one died of metastatic and local disease, and two are alive 13 months and 8 years after wide resection. We conclude that these neoplasms form a distinctive subset of pediatric soft tissue sarcomas that display an aggressive clinical behavior, typically with local recurrence, and exhibit features of myofibroblastic differentiation.

We report detailed immunological, cytogenetic and molecular evidence for complete identity of the leukemic cell populations in monozygotic female twins with concordant leukemia diagnosed at two months of age. Both infants had early pre-B acute lymphoblastic leukemia with the (11;19)(q23;p13) chromosomal translocation. A common clonal origin of leukemia in these infants was suggested by the finding of identical oligoclonal heavy chain immunoglobulin gene rearrangements. Leukemic cell DNA was examined for 11q23 rearrangements by Southern blotting and restriction fragments of identical size were found in the two cases, in contrast to the diversity of rearrangements observed in other unrelated and nontwinned control infants with t(11;19)(q23;p13). Similar restriction fragments were absent in blood mononuclear DNA from both parents, liver tissue from one twin and remission bone marrow of the other, indicating that the 11q23 rearrangement was acquired and not inherited as a chromosomal abnormality or polymorphism. These findings provide a definitive evidence for intrauterine single cell origin, with twin to twin transmission, of concordant leukemia in this infant twin pair.

Purpose: To evaluate the immunophenotypes, karyotypes, and clinical features, including treatment responses, of patients with childhood acute lymphoblastic leukemia (ALL) and either a t(1;19)(q23;p13) or a der(19)t(1;19)(q23;p13) translocation., Patients and Methods: The lymphoblasts of 45 patients with a balanced translocation, t(1;19) or its derivative form, der(19)t(1;19), were analyzed by cytogenetic and immunologic methods for differences that might suggest distinct subtypes of ALL. This cohort was treated in four consecutive clinical trials with a median overall follow-up duration of 7 years., Results: A pre-B immunophenotype was found in 10 cases with the balanced t(1;19) and 31 with the unbalanced der(19)t(1;19). The four remaining cases, each with a derivative t(1;19), were classified as early pre-B ALL. The characteristic surface antigen profile of the 41 pre-B cases was CD19+/CD10+/CD22+/CD34-/CD20+/-, whether the translocation was balanced or derivative. In contrast to the four early pre-B cases, which had hyperdiploid karyotypes (> 50 chromosomes), the pre-B cases were primarily pseudodiploid. Comparison of presenting clinical and laboratory features, as well as event-free survival, failed to disclose any differences that would warrant separation of pre-B cases with a balanced or derivative translocation. However, neither subgroup responded to therapy as well as patients with early pre-B ALL, each of whom remains in complete remission for > or = 3 years., Conclusion: The t(1;19) and the der(19)t(1;19) identify a relatively homogeneous group of patients with pre-B ALL, who can be expected to respond similarly to intensive chemotherapy. The exceptional cases have an early pre-B phenotype with hyperdiploid karyotypes and appear to have favorable prognosis.

Central nervous system (CNS) relapse confers a poor prognosis in children with acute lymphoblastic leukemia (ALL). It is uncertain whether morphologically undetectable leukemia is present in the bone marrow at the time of CNS relapse, or whether the CNS acts as a 'sanctuary' site to allow reseeding of the marrow at a later time. We examined DNA from bone marrow samples from six patients with T-cell ALL with isolated CNS relapse using sensitive polymerase chain reaction (PCR) assays to detect minimal residual disease. One of these PCR assays was based on amplification of leukemia-specific TCR-delta gene rearrangements, while the other assay relied upon detection of the c-tal deletion. In four patients, where bone marrow samples were taken at the time of CNS relapse, residual disease was detectable in every sample at a level below morphological detection. In addition, three patients had residual disease detected in their subsequent bone marrow when CNS disease was not evident. Our findings, although preliminary, suggest that relapse of leukemia in the CNS reflects resurgence of the disease in the bone marrow that is first detected clinically in the CNS. The concomitant molecular detection of bone marrow leukemia at time of 'isolated' CNS relapse in children with T-cell ALL explains subsequent bone marrow relapse in some of these children, and argues for intensive systemic therapy of these patients.

Purpose: Leukemic cell characteristics were analyzed in infants less than 1 year of age with acute lymphoblastic leukemia (ALL) to determine adverse prognostic factors that might explain the poor prognosis of this group., Patients and Methods: Treatment outcomes were analyzed according to the presenting clinical and laboratory features of 30 infants treated between May 1979 and April 1993. A stepwise multivariate regression model was used to identify the most important prognostic indicator with respect to event-free survival., Results: Infant ALL cases were characterized by high presenting leukocyte count (median, 87 x 10(9)/L), increased frequency of CNS leukemia (50%), and blast cells with a CD10- phenotype (67%), myeloid-associated antigen expression (48%), and 11q23/MLL rearrangement (68%). The 11q23/MLL involvement was correlated with age less than 6 months, CD10- phenotype, myeloid-associated antigen expression, and high leukocyte count. Although 11q23/MLL involvement, age less than 6 months, myeloid-associated antigen expression, and female sex were each significantly associated with an inferior treatment outcome, only rearranged 11q23/MLL emerged as an independent predictor of prognosis in multivariate analysis (P = .01). Infants with this genetic abnormality had a 4.7-fold (95% confidence interval, 1.3- to 17.0-fold) increased risk in adverse events compared to other infants., Conclusion: The 11q23/MLL involvement of blast cells identifies a major subgroup of infant ALL cases that require an innovative treatment approach. Infants who lack this genetic abnormality have an intermediate prognosis and could be treated accordingly on risk-directed protocols.

Tretinoin is effective in acute promyelocytic leukaemia in adults. Data about its efficacy and safety in children are limited. We have treated 9 children with tretinoin at 45 mg/m2 per day. Pseudotumour cerebri or hyperleucocytosis occurred in 5 patients. Retinoic acid syndrome was seen in 3 cases. 1 of 2 children who developed hyperleucocytosis, pseudotumour cerebri, and retinoic acid syndrome died despite steroids and mechanical ventilation. Complete remissions with tretinoin alone were achieved in 15 patients. All 8 surviving children received consolidation chemotherapy. Our experience with tretinoin therapy suggests that toxicity is frequent in children.

Background: Treatment of the central nervous system is crucial to the successful treatment of acute lymphoblastic leukemia in children. The intensity and timing of the therapy are based on the presence or predicted risk of central nervous system leukemia as assessed according to criteria that remain controversial., Methods: The clinical importance of leukemic blast cells detected in cerebrospinal fluid at the time of diagnosis was evaluated in 351 children with acute lymphoblastic leukemia in a randomized trial of intensive chemotherapy. All patients received intrathecal chemotherapy during the first year. Patients considered to be at high risk of relapse because of their clinical and cytogenetic features also received cranial irradiation and intrathecal chemotherapy one year after remission. Patients were considered to have central nervous system leukemia at diagnosis if they had at least 5 leukocytes per microliter of cerebrospinal fluid, with leukemic blast cells apparent in cytocentrifuged preparations, or cranial-nerve palsy; they received additional intrathecal injections of chemotherapeutic agents and cranial irradiation. Patients were retrospectively classified on the basis of cerebrospinal fluid findings: 291 patients had no detectable blast cells, 42 had fewer than 5 leukocytes per microliter and blast cells, and 18 had central nervous system leukemia as defined above. The clinical characteristics and outcomes of treatment in these groups were analyzed., Results: The five-year probability of survival free of relapses confined to the central nervous system in patients with detectable blast cells and fewer than 5 leukocytes per microliter of cerebrospinal fluid was lower than in patients without blast cells (mean [+/- SE], 87 +/- 13 vs. 96 +/- 2 percent), but was not different from the probability in patients with central nervous system leukemia at diagnosis. All such isolated relapses of leukemia in patients with detectable blast cells occurred during the first year of treatment, before scheduled cranial irradiation. In a multivariate analysis, the presence of cerebrospinal fluid blast cells with fewer than 5 leukocytes per microliter was independently related to the risk of relapse confined to the central nervous system., Conclusions: Patients with leukemic blast cells in their cerebrospinal fluid are at increased risk for central nervous system relapse when cranial irradiation is delayed. Such patients require intensified central nervous system treatment early in the course of therapy.

The independent significance of CD10 expression in childhood acute lymphoblastic leukemia (ALL) is uncertain because most studies have not adjusted for other risk features, such as age and immunophenotype, or for treatment effects. We reassessed the clinical importance of CD10 expression in patients who received highly effective contemporary treatment. CD10 antigen was detected in blast cells from 384 of 408 patients (94%) with B-lineage ALL and 36 of 90 (40%) with T-cell ALL. In the B-lineage subgroup, CD10 expression was associated with favorable presenting features: age > or = 1 year, lower leukocyte count (< 50 x 10(9)/l), and leukemic cell DNA index > or = 1.16 or hyperdiploidy > 50 chromosomes. One-half of the patients with CD10- B-lineage ALL had 11q23 chromosomal abnormalities. Separate analysis of the marker in T-cell ALL revealed no differences between CD10+ and CD10- cases in clinical features or karyotypic patterns, with the exception of a lower frequency of central nervous system leukemia and a higher frequency of 9p abnormalities in the former subgroup. CD10+ T-cell cases were also significantly more likely than CD10- cases to coexpress CD21, CD1, CD4, or CD8. Lack of CD10 expression was independently associated with an adverse prognosis in T-cell ALL (p = 0.02). However, for the larger subgroup of patients with B-lineage ALL, CD10 expression has no independent prognostic significance.

Fourteen children (ages 2-15 years) with acute leukemia in relapse were treated with daily recombinant interferon gamma for 14 days by subcutaneous injections at fixed dose levels of 0.1, 0.25, 0.5, or 0.75 mg/m2 (1.0, 2.5, 5.0, or 7.5 x 10(6) units/m2) without intrapatient escalation. Patients received a second 14-day course of therapy followed by thrice weekly administration unless there were signs of progressive disease or grade 3 or 4 toxicity. Side effects in the 13 evaluable patients included fever (n = 10), fatigue (9), decreased Karnofsky performance score (8), hypertriglyceridemia (8), myalgia (5), weight loss > 5% (4), elevated liver transaminases (4), and abdominal pain (3). There was only one grade 4 toxicity: one of the six patients at the 0.5 mg/m2 dose level developed reversible acute renal failure. One patient died of gastrointestinal hemorrhage due to disease-related refractory thrombocytopenia. One child had an oncolytic response and two others stable disease for 138 and 148 days. An appropriate dose level for phase II studies in children is 0.5 mg/m2 per day.

We report a 15-year-old boy diagnosed with acute lymphoblastic leukemia (ALL) in 1983. Induction therapy included L-asparaginase. After the second dose of L-asparaginase, he had a left sided focal seizure and computed tomography (CT) scan of the head showed a right frontal infarct. No further L-asparaginase was given. Complete remission was achieved and he successfully completed therapy in 1986. Eight months later he had an isolated bone marrow relapse. Reinduction therapy included L-asparaginase. After the fourth dose of L-asparaginase, he presented with severe headache and a CT scan showed a right temporal infarct. Repeat infarction on rechallenge with L-asparaginase has not been previously reported. Prophylactic therapy, such as fresh frozen plasma, should be considered before patients, with a previous cerebral insult, are rechallenged with L-asparaginase. However the effectiveness of such therapy has not been established.

Prompted by evidence that Langerhans cell histiocytosis (LCH) is a nonmalignant disorder of immune regulation, we used cyclosporine (12 mg/kg/d orally) to treat three young children with advanced multisystem LCH. All three patients had partial responses to cyclosporine within 2 months of therapy, as evidenced by complete resolution of organ dysfunction and regression of the majority of lesions. Complete responses were attained by adding relatively nontoxic chemotherapy (ie, prednisone and vinblastine). Toxicity from cyclosporine comprised mild and reversible elevations of the serum creatinine and blood urea nitrogen. These results indicate that further evaluation of cyclosporine for the treatment of patients with advanced LCH is warranted.