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BACKGROUND The Childhood Cancer Research Network (CCRN) was established within the Children's Oncology Group (COG) in July 2008 to provide a centralized pediatric cancer research registry for investigators conducting approved etiologic and survivorship studies. The authors conducted an ecological analysis to characterize CCRN catchment at >200 COG institutions by demographic characteristics, diagnosis, and geographic location to determine whether the CCRN can serve as a population-based registry for childhood cancer. METHODS During 2009 to 2011, 18,580 US children newly diagnosed with cancer were registered in the CCRN. These observed cases were compared with age-specific, sex-specific, and race/ethnicity-specific expected numbers calculated from Surveillance, Epidemiology, and End Results (SEER) Program cancer incidence rates and 2010 US Census data. RESULTS Overall, 42% of children (18,580 observed/44,267 expected) who were diagnosed with cancer at age

BACKGROUND To evaluate whether progress continues in identifying more effective treatments for children and adolescents with cancer, the authors examined both overall and disease-specific childhood cancer mortality rates for the United States, focusing on data from 2000 to 2010. METHODS Age-adjusted US mortality trends from 1975 to 2010 were estimated using joinpoint regression analysis. Analyses of annual percentage change (APC) were performed on the same diagnostic groupings for the period restricted to 2000 through 2010 for groupings ages 45,000 cancer deaths averted through 2010. CONCLUSIONS Cancer mortality for both children and adolescents declined from 2000 to 2010, with significant declines observed for multiple cancer types. However, greater than 1900 cancer deaths still occur each year among children and adolescents in the United States, and many survivors experience long-term effects that limit their quality of life. Continued research directed toward identifying more effective treatments that produce fewer long-term sequelae is critical to address these remaining challenges. Cancer 2014;120:2497–2506. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.

Background Depression is common during and after breast cancer treatment. However, the role of specific therapeutic modalities and related biological mechanisms remains unclear. Radiation is an essential component of breast conserving therapy and may contribute to depression in breast cancer patients through activation of inflammatory pathways.

BACKGROUND Limited data exist on the comprehensive assessment of late medical and social effects experienced by survivors of childhood and young adult acute myeloid leukemia (AML). METHODS This analysis included 272 5-year AML survivors who participated in the Childhood Cancer Survivor Study (CCSS). All patients were diagnosed at age ≤21 years between the years 1970 and 1986, and none underwent stem cell transplantation. Rates of survival, relapse, and late outcomes were analyzed. RESULTS The average follow-up was 20.5 years (range, 5–33 years). The overall survival rate was 97% at 10 years (95% confidence interval [95%CI], 94%–98%) and 94% at 20 years (95% CI, 90%–96%). Six survivors reported 8 recurrences. The cumulative incidence of recurrent AML was 6.6% at 10 years (95% CI, 3.7%–9.6%) and 8.6% at 20 years (95% CI, 5.1%–12.1%). Ten subsequent malignant neoplasms (SMN) were reported, including 4 with a history of radiation therapy, for a 20-year cumulative incidence of 1.7% (95% CI, 0.02%–3.4%). Six cardiac events were reported, for a 20-year cumulative incidence 4.7% (95% CI, 2.1%–7.3%). Half of the survivors reported a chronic medical condition and, compared with siblings, were at increased risk for severe or life-threatening chronic medical conditions (16% vs 5.8%; P < .001). Among those aged ≥25 years, the age-adjusted marriage rates were similar among survivors and the general United States population (57% for both) and lower compared with siblings (67%; P < .01). Survivors' college graduation rates were lower compared with siblings but higher than the general population (40% vs 52% vs 34%, respectively; P < .01). Employment rates were similar between survivors, siblings, and the general population (93%, 97.6%, and 95.8%, respectively). CONCLUSIONS Long-term survival from childhood AML ≥5-years after diagnosis was favorable. Late-occurring medical events remained a concern with socioeconomic achievement lower than expected within the individual family unit, although it was not different from the general United States population. Cancer 2008. © 2008 American Cancer Society.

BACKGROUND The Children's Oncology Group (COG), a merger of the Children's Cancer Group (CCG) and the Pediatric Oncology Group (POG), conducts clinical trials for the treatment of childhood cancer. To assess the feasibility of developing a nationwide childhood cancer registry, the authors attempted to determine whether COG could serve as a resource for identifying all children with cancer. METHODS A consolidated file of children age < 20 years who were diagnosed with cancer between 1992–1997 and registered with either CCG or POG was linked with records from the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) Program. Age-specific registration rates and age-adjusted registration rates (AARR) were calculated overall and by year of diagnosis, gender, race/ethnicity, stage of disease at diagnosis, and type of cancer. RESULTS Of 10,108 children age < 20 years with cancer who were identified by the 11 SEER registries between 1992–1997, 5796 were registered with CCG or POG. The AARR was 71% for children age < 15 years, 24% for adolescents ages 15–19 years, and 57% for children age < 20 years. Registration rates were stable over the years studied, varied by geographic region, and were found to be higher among children with more advanced disease. Registration rates were highest for children with leukemia, hepatic tumors, and renal tumors, and were lowest for carcinoma and retinoblastoma. CONCLUSIONS The results of the current study demonstrate that not all children with cancer are registered by the cooperative groups; however, a national registry program can be achieved by supplementing cases identified through COG with data collected by statewide population-based cancer registries. Such a partnership would be mutually beneficial, allowing COG to achieve 100% registration of children with cancer and, for the statewide cancer registries, improving the timeliness of case-finding and follow-up information for cancer outcomes. Cancer 2003;97:1339–45. © 2003 American Cancer Society. DOI 10.1002/cncr.11192

BACKGROUND Recurring breakpoints in chromosome bands 15q13-15 occur infrequently in leukemia. To the authors' knowledge, the clinical significance of these breakpoints in childhood acute lymphoblastic leukemia (ALL) has not been previously investigated. METHODS Centrally reviewed karyotypes of children with newly diagnosed ALL enrolled on Children's Cancer Group protocols from 1988 to 1995 formed the basis of the current report. Statistical analyses used chi-square tests for homogeneity of proportions, and outcome was analyzed using life table methods and associated statistics. RESULTS Of 1946 cases with centrally reviewed and accepted cytogenetic analyses, 23 cases (1%) had breakpoints in chromosome bands 15q13-15. Most patients with 15q13-15 breakpoints had standard risk ALL, although breakpoints in 15q13-15 occurred more frequently in infants than in older children. The majority of these patients (16 patients; 70%) had balanced 15q13-15 rearrangements. Additional chromosomal abnormalities not involving 15q included abnormal 12p, abnormal 9p, Philadelphia chromosome, deletion 6q, and an 11q23 breakpoint. Thirteen (57%) 15q13-15 breakpoints occurred in pseudodiploid karyotypes; five (22%) were in hyperdiploid karyotypes with 47-50 chromosomes; two (9%) were in hyperdiploid karyotypes with > 50 chromosomes; and three (13%) were in hypodiploid karyotypes. Of the 23 patients with 15q13-15 breakpoints, 21 were survivors, 18 survived event-free for 2.2-9.3 years, and 3 were alive 1 to 3 years after a relapse at time of writing. CONCLUSIONS The current study suggests that genes at 15q13-15 may be involved in the leukemogenesis of some cases of childhood ALL, but that with current intensive therapy such aberrations do not confer increased risk of treatment failure. Cancer 2002;94:1102–10. © 2002 American Cancer Society. DOI 10.1002/cncr.10325

BACKGROUND CI-958 is a synthetic intercalating agent of a new chemical class, the benzopyranoindazoles, with promising preclinical activity. Its mechanism of action is thought to be stabilization of the cleavable complex of DNA with topoisomerase II, as well as DNA helicase blockade. It is thought to have less cardiotoxicity than the anthracyclines. Early Phase I studies in adults showed the drug to be well tolerated, making it an attractive agent to pursue in Phase I clinical trials in children. METHODS Children and adolescents with recurrent solid tumors received CI-958 at an initial dose of 450 mg/m2 over 2 hours. Dose escalation was performed in a standard fashion in cohorts of three patients until dose limiting toxicity and the maximum tolerated dose were determined. RESULTS Twenty-one patients were entered on the study. The maximum tolerated dose was found to be 650 mg/m2. Dose limiting toxicities were Grade 4 neutropenia and Grade 4 hypotension at the dose level of 700 mg/m2. CONCLUSIONS The maximum tolerated dose of CI-958 in children and adolescents is 650 mg/m2. No antitumor activity has been observed. Cancer 2001;91:1166–9. © 2001 American Cancer Society.

BACKGROUND Infants diagnosed with acute lymphoblastic leukemia (ALL) are considered the patient subgroup at the highest risk for central nervous system (CNS) disease, both at presentation and as an isolated extramedullary relapse. In addition, they are highly vulnerable to adverse developmental sequelae from CNS-directed therapy. METHODS Thirty patients younger than 12 months at diagnosis (12 males, 18 females) in first hematologic remission were evaluated after completion of ALL therapy (mean age = 62.1 months; standard deviation = 17.2 months; range = 38–102 months). CNS-directed treatment included very high dose infusions of methotrexate (MTX) and intrathecal cytarabine and MTX. Three patients had meningeal leukemia that required additional therapy. Children were administered the McCarthy Scales of Children's Abilities, and parents completed a sociodemographic questionnaire to obtain information about occupation and education. RESULTS Mean scores on all 6 cognitive and motor indices of the McCarthy Scales were in the average range (Verbal = 52.0; Perceptual = 53.6; Quantitative = 49.6; General Cognitive Index [GCI] = 102.1; Memory = 49.2; Motor = 51.0). Score distributions for each neurodevelopmental index were comparable to age-based population standards. One patient obtained a GCI that exceeded 2 standard deviations above the mean; none scored more than 2 standard deviations below. There was no report of developmental disabilities or neurologic disorders for any of the patients. Risk factors, including age at diagnosis, gender, additional CNS-directed treatment, and family socioeconomic status, were not associated with developmental outcome. CONCLUSIONS Test findings indicated a generally positive neurodevelopmental outcome for ALL patients diagnosed in infancy who were treated with very high dose MTX as CNS-directed therapy. Combined with the reduction in the isolated CNS relapse rate achieved by the Children's Cancer Group (CCG) clinical trial CCG-107, the results of this study represent a substantial improvement in neurodevelopmental outcome for very young patients compared with infants treated for ALL in the past. Cancer 1999;85:1859–65. © 1999 American Cancer Society.

BACKGROUND Children with Philadelphia (Ph) chromosome positive (+) acute lymphoblastic leukemia (ALL) represent a subgroup at very high risk for treatment failure. In this report, the authors assessed the outcome of Ph+ ALL in a large cohort of children treated on contemporary intensive chemotherapy protocols of the Children's Cancer Group (CCG). METHODS This study included 1322 children enrolled between 1988-1995 on CCG risk-adjusted studies for ALL who had centrally reviewed cytogenetic data. Thirty patients had a t(9;22)(q34;q11) translocation and were referred to as Ph+; 1292 were Ph negative(-). Outcome analyses used standard life table methods. RESULTS Compared with Ph- ALL patients, Ph+ ALL patients were more likely to be black (P = 0.008), age >10 years (P = 0.02), and have a leukocyte count ≥50,000/L (P < 0.0001). Nearly all Ph+ (96.7%) and Ph- (98.3%) patients achieved remission after induction therapy, yet event free survival outcome was significantly worse for Ph+ patients compared with Ph- patients, with 4-year estimates of 20.1% (standard deviation [SD] = 9.1%) and 75.8% (SD = 1.2%), respectively (P < 0.0001). This difference was maintained among patients regardless of presenting leukocyte count, age, or early response to therapy. Ten Ph+ patients underwent bone marrow transplantation (BMT) at the time of first remission; six of these patients remained event free at the time of analysis, and represent the majority (six of eight) of patients surviving event free. CONCLUSIONS The findings of the current study confirm that Ph chromosome positivity represents a significant independent adverse risk factor for childhood ALL that has not been abrogated by current intensive chemotherapy programs. BMT at the time of first remission, as well as other alternative strategies employing biotherapeutic agents, should be considered in future front-line trials for pediatric patients with Ph+ ALL. Cancer 1998;83:2030-2039. © 1998 American Cancer Society.

BACKGROUND This Phase I trial was developed to determine the safety, biologic activity, and effects on hematopoietic recovery of PIXY321 following ifosfamide, carboplatin, and etoposide chemotherapy for children with recurrent or refractory solid tumors. METHODS Children (age < 22 years at diagnosis) received ifosfamide 1800 mg/m2/day x 5 days, carboplatin 400 mg/m2/day x 2 days, and etoposide 100 mg/m2/day x 5 days, followed by daily subcutaneous administration of PIXY321. Dose-limiting toxicity was defined as Grade IV toxicity related to PIXY321. Pharmacokinetic and endogenous cytokine production studies were conducted during Course 1, and peripheral blood (PB) progenitor cell and receptor expression studies were conducted during Course 1 when the white blood cell count recovered to ≥1000/mm3. RESULTS Twenty-four children received ifosfamide, carboplatin, and etoposide chemotherapy plus PIXY321, the latter at doses of 500 μg/m2/day (n = 3), 750 μg/m2/day (n = 6), 1000 μg/m2/day (n = 9), or 500 μg/m2/twice a day (n =6). PIXY321 was well tolerated, with only 1 dose-limiting toxicity (chills, occurring at a dose of 750 μg/m2/day). The maximum tolerated dose was not reached in this study. The median days to absolute neutrophil count recovery (≥1000/mm3) and platelet recovery (>100,000/mm3) during Course 1 following PIXY321 (1000 μg/m2/day) were 22 days (range, 5-33 days) and 20 days (range, 5-31 days), respectively. There was a 2500, 5000, 3000, and 390% increase in PB granulocyte-macrophage colony-forming units, erythrocyte blast-forming units, granulocyte erythrocyte macrophage and megakaryocyte colony-forming units, and CD34+ cells, respectively. CONCLUSIONS In summary, this pediatric Phase I trial demonstrated that PIXY321 was well tolerated by children and resulted in platelet recovery a median of 20 days after ICE chemotherapy and an increase in the number of PB progenitor cells above baseline. However, based on recent negative results with PIXY321 in randomized Phase II/III trials involving adult subjects, PIXY321 is not currently available for future trials involving children. Cancer 1998;83:1449-1460. © 1998 American Cancer Society.

BACKGROUND During the decade between 1980-1990, the rate of cancer in children in the U.S. increased. It is unknown whether cancer in infancy, which is biologically and clinically different from cancer in older children, also increased. METHODS To evaluate changes in cancer incidence in infants in the U.S. age < 1 year, data from the Surveillance, Epidemiology, and End Results (SEER) program and the U.S. Bureau of the Census were used to construct age specific, population-based cancer incidence rates. RESULTS Overall, the annual cancer rate in infants increased from 189 cases per million infants between 1979-1981 to 220 between 1989-1991. At both timepoints, female infants had higher cancer rates than male infants. Although the rates for female infants remained stable at 223 between 1979-1981 versus 236 between 1989-1991, rates for male infants increased from 158 to 205 during the same timepoints. Male infants had increased rates of central nervous system (CNS) tumors (P < 0.05), neuroblastoma, and retinoblastoma; female infants had increased rates of teratomas (P < 0.01) and hepatoblastomas. Between 1979-1981, the three most common types of cancer in infants were neuroblastoma, leukemia, and renal tumors (27%, 15%, and 14%, respectively), and were neuroblastoma, CNS tumors, and leukemia between 1989-1991 (27%, 15%, and 13%, respectively). CONCLUSIONS This study shows that the rate of certain types of cancer in infants in the U.S. is increasing. Studies of both genetic and environmental factors are needed to explain these increased rates and the changing distribution of cancer in the first year of life. Cancer 1998;82:1396-400. © 1998 American Cancer Society.

BACKGROUND Early response to therapy is defined as the initial response prior to Day 28 of treatment, the conventional time of marrow evaluation. The number of reports linking early response to therapy with the ultimate outcome of childhood acute lymphoblastic leukemia is substantial and growing. When this study began, these experiences had yet to be comprehensively reviewed. METHODS A comprehensive search of the published literature yielded contributory reports of 14 trials conducted in the United States and Europe. In addition, unpublished data from one Children's Cancer Group trial were made available. Outcome measures were standardized by conversion to ratios of the incidence of adverse events among poorer and better responders. RESULTS Early response to therapy was an independent prognostic factor in each of the 15 trials, which together included more than 10,000 patients. The incidence of slower early response ranged from 2-33%, with various measures and criteria used in different trials. Patients with a slower early response were 1.5-6.1 times (median, 2.7) more likely to have an adverse event than patients with a more rapid early response, however defined. Early response maintained prognostic significance after the exclusion of induction failure and within risk strata defined by age, white blood cell count, and/or immunophenotype. Its significance was also maintained in multivariate analyses where performed. CONCLUSIONS Early response to therapy, whether determined by evaluation of bone marrow or peripheral blood, is a consistent, independent prognostic factor in childhood acute lymphoblastic leukemia. Slower early response may serve as a useful surrogate for outcome, a more complex end point, in investigations of the cellular and molecular determinants of resistance to therapy. It may also allow early identification of a patient subpopulation for whom current therapy is less effective and alternative strategies may be justified. Cancer 1997; 80:1717-26. © 1997 American Cancer Society.

BACKGROUND The murine monoclonal antibody (MoAb) 14.G2a recognizes GD2, a disialoganglioside expressed in tumors of neuroectodermal origin, and facilitates antibody dependent cellular cytotoxicity (ADCC) in vitro. When given in vivo, interleukin-2 (IL-2) can increase ADCC by enhancing the activity and number of circulating lymphocytes. METHODS Thirty-three pediatric patients with GD2 positive malignancies, ranging in age from 2 to 17 years (median, 9.9 years), received IL-2 and 14.G2a in this Phase I/IB study of the Children's Cancer Group (CCG) and were monitored for toxicities and response to therapy. Seven of these patients also received granulocyte-macrophage-colony stimulating factor. RESULTS The maximum tolerated dose (MTD) of 14.G2a with IL-2 was 15 mg/m2/day. The most prevalent Grade 3-4 toxicities were generalized pain (n = 14 [42%]) and fever without documented infection (n = 17 [52%]). IL-2 was thought to be the causative agent in most cases of fever. Toxicities attributed to 14.G2a included pain, allergic or anaphylactic reactions, and rash. Human antimouse antibodies were demonstrated in 9 of 21 evaluated patients. One patient with neuroblastoma had a partial response, and one patient with osteosarcoma had a complete response. Immunocytology demonstrated that the number of neuroblastoma cells in bone marrow decreased in three patients. CONCLUSIONS The murine MoAb 14.G2a was well tolerated at the MTD and appeared to have some antitumor activity. Further development of this approach will involve additional engineered forms of the antibody as well as testing in the adjuvant and minimal residual disease setting. Cancer 1997; 80:317-33. © 1997 American Cancer Society.

the Medical Re- search Council Human Genetics Unit (Edin- burgh, United Kingdom) for the molecular anal- yses. Address for reprints: H. Stacy Nicholson, M.D., Department of Hematology/Oncology, Children’s National Medical Center, 11 1 Michigan Avenue, N.W., Washington, DC 20010. Received January 22, 1996; revision received May 14, 1996; accepted May 14, 1996.

BACKGROUND Topotecan is a topoisomerase I inhibitor that has good penetration across the blood-brain barrier and significant antitumor activity against human brain tumor xenografts. In a Phase I trial in children with refractory cancer, topotecan was well tolerated when administered as a 24-hour infusion. The maximum tolerated dose was 5.5 mg/m2 and the dose-limiting toxicity was myelosuppression. This Phase II study of topotecan was performed to assess the activity of topotecan against childhood brain tumors. METHODS Forty-five children with either a previously treated primary brain tumor that was refractory to standard therapy, or an untreated brain stem glioma or glioblastoma multiforme, received topotecan administered as a 24-hour intravenous infusion every 21 days. The initial dose was 5.5 mg/m2 with escalation to 7.5 mg/m2 on the second and subsequent doses in patients who did not experience dose-limiting toxicity. RESULTS There were no complete or partial responses in the patients with high grade glioma (n = 9), medulloblastoma (n = 9), or brain stem glioma (n = 14). One of 2 patients with a low grade glioma had a partial response lasting more than 17 months; 3 patients with a brain stem glioma had stable disease for 12 to 28 weeks; and 1 patient with a malignant neuroepithelial tumor and 1 patient with an optic glioma had stable disease for 41 weeks and 22 weeks, respectively. Dose esalation from 5.5 mg/m2 to 7.5 mg/m2 was well tolerated in the first 11 patients enrolled on this study who had not received prior craniospinal radiation therapy. The starting dose was subsequently increased to 7.5 mg/m2 for patients without prior craniospinal radiation. CONCLUSIONS Topotecan administered as a 24-hour infusion every 21 days is inactive in high grade gliomas, medulloblastomas, and brain stem tumors. Cancer 1996;78:527-31.

BACKGROUND It is not known if therapy for acute lymphoblastic leukemia (ALL) during childhood increases the risk of birth defects in the offspring of adult survivors. The Childrens Cancer Group (CCG), in collaboration with the National Institutes of Health (NIH), conducted a retrospective cohort study of adults successfully treated for childhood ALL to determine if their offspring had an increased incidence of birth defects compared with the offspring of their sibling controls. METHODS Study subjects were patients who had been enrolled on CCG ALL protocols, who were treated for ALL prior to age 20, who survived at least 2 years, and who were at least age 18. Survivors (N = 593) and sibling controls (N = 409) were interviewed by telephone. RESULTS The mean age of survivors was 22.6 years; the mean age of controls was 25.2 years. Among survivors, 93 (15.7%) had given birth to or fathered a total of 140 live-born offspring, (mean age, 3.4 years), and 122 (29.8%) sibling controls had given birth to or fathered a total of 228 live-born offspring (mean age, 5.9 years). There was no difference in the rate of birth defects between offspring of survivors and offspring of controls (3.6% [5 of 140] vs. 3.5% [8 of 228]; relative risk, 1.02; 95% confidence interval, 0.34, 3.05). No specific ALL therapy was associated with an increased rate of birth defects. Only female survivors reported offspring with birth defects (P = 0.0735). CONCLUSIONS Adult survivors of childhood ALL in our study were not at greater risk for having offspring with birth defects compared with sibling controls. Although this is the largest group of ALL survivors studied to date, the number of offspring is still not large enough to detect small but significant differences in rare events such as birth defects. Studies following this cohort into later adulthood and studies of additional ALL survivors are necessary to adequately quantify the risks. Cancer 1996;78:169-76.

Background. Recombinant human Interleukin-2 (IL-2) has been effective at inducing measurable antitumor responses in adults with renal cell carcinoma and melanoma. It also is being tested as adjuvant therapy for patients with acute myeloid leukemia after autologous bone marrow transplantation. Methods. The authors tested IL-2 in a pediatric Phase II trial using a regimen that has antitumor effects in adults and was proven to be tolerated acceptably in a prior Phase I pediatric trial. Thirty-eight patients were entered into this study of whom 36 received IL-2 and were evaluable (20 with sarcoma, 9 with neuroblastoma, 5 with renal cell carcinoma, and 1 each with melanoma and lymphoma). Results. Interleukin-2 dose modifications were based on tolerance and toxicity, such that 46% of these patients received a 50% increase in IL-2 dose during the second week, and 81% of those receiving the elevated dose continued receiving this dose level during the third week of treatment. A single patient with renal cell carcinoma had a complete response that was maintained ; the remaining 35 patients did not show objective evidence of tumor response sufficient to qualify as either a complete response or a partial response. Conclusions. Absolute lymphocyte counts were indicative of the immunostimulatory effect of this IL-2 regimen as observed for adults, with a median 7.2-fold increase. Nevertheless, despite immune activation, a sufficient number of patients were evaluated, indicating that IL-2 does not have measurable antitumor effects in children with large refractory sarcomas or neuroblastomas, whereas one of five children with renal cell carcinoma had a complete response, consistent with the 10-20% response rate observed in adults.

Background. Both thiotepa and its active metabolite, tepa, efficiently cross the blood-brain barrier. After intravenous administration, the cerebrospinal fluid concentrations achieved are nearly identical to those in olasma. This provides a strong rationale for testing this agent against brain tumors. Methods. Sixty pediatric patients with recurrent primary brain tumors were treated on a multiinstitutional Phase II study of intravenous thiotepa at a dose of 5 mg/m2 administered every 3 weeks. This dose is the result of a prior pediatric Phase I trial and is significantly higher than those previously recommended. Results. Three of 13 assessable patients with medul-oblastoma had partial responses lasting 22, 25, and 54 weeks. Although no objective responses were observed in 6 assessable patients with malignant gliomas and 14 with brain stem gliomas, 5 of 16 and 4 of 14 patients in elese respective strata had prolonged periods of stable isease (SD) lasting from 12 to more than 33 weeks. Nine ssessable patients with ependymoma had no objective esponse, but two had SD, both for more than 33 weeks. Myelosuppression was the principle toxic effect encoun-ered and appeared to be more severe in patients who had received prior craniospinal radiation therapy or nitro-urea therapy. Conclusions. By conventional Phase II criteria, thiotepa appears to have activity in medulloblastoma. Based on several patients with prolonged SD, it also may possess some limited activity in brain stem and malignant gliomas. The steep in vitro dose-response curve of thiotepa and the long durations of response or SD observed with the dose reported here suggest that moderate-dose to high-dose thiotepa with cytokine support or autologous bone marrow rescue may be associated with an improved response rate to this agent. Cancer 1993; 72:271–5.

Multivariate analyses of the clinical course of 1537 children with acute lymphoblastic leukemia (ALL) identified a subgroup which experienced short remission duration and a high incidence of extramedullary relapse. The patients differed from other ALL patients by the presence at diagnosis of two or more of a constellation of clinical and laboratory features: organomegaly or mass disease, E-rosette positivity, hemoglobin level greater than 10 g/dl, leukocyte count greater than 50,000/microliters, male predominance, and older age. This type of presentation of ALL is referred to as the "lymphoma syndrome" (LS) since such patients exhibit a pattern of several clinical and laboratory features which were observed repeatedly but in differing combinations, and some of which clinically resemble lymphoma. A subsequent database from 2231 patients was analyzed. Patients with a mediastinal mass, massive splenomegaly, or massive adenopathy, alone or in combination, had a worse outcome when the patient also had either leukocytosis, E-rosette-positive lymphoblasts, or a normal or near normal hemoglobin (Hb) level at diagnosis. Similarly, the above three laboratory features alone or in combination did not predict less than 40% disease-free survival (DFS) unless they were accompanied by at least one of the clinical features of mass disease. When at least one clinical feature and at least one laboratory feature were present, the overall DFS was 36% 6 years after diagnosis versus 64% for all other patients. The association of these features with poor prognosis remained significant after adjusting for the level of leukocyte count at diagnosis, age at diagnosis, and sex of the patients. Patients with this recurrent syndrome of features do not represent a homogeneous biologic entity but they constitute a subgroup of patients with ALL having a high risk of treatment failure using current therapies, including failure to achieve remission, early relapse, and increased frequency of relapse in extramedullary sites. They deserve early recognition at diagnosis and selection of treatment strategies appropriate for very high risk ALL.

BACKGROUND. Effective chemotherapy is lacking for most types of central nervous system (CNS) tumors in children. Temozolomide, an agent with activity against adult brain tumors, was investigated in children and adolescents with recurrent CNS tumors. METHODS. Temozolomide was administered orally as monthly 5-day courses at doses of 200 mg/m 2 /d (patients with no prior craniospinal irradiation [CSI]) or 180 mg/m 2 /d (prior CSI). Patients with a complete (CR) or partial (PR) response or stable disease (SD) could continue temozolomide for up to 12 cycles. RESULTS. The cohort comprised 122 patients, including 113 with CNS tumors. Median age was 11 years (range, 1–23 years). Among 104 evaluable patients with CNS tumors, 5 PRs and 1 CR were observed. PRs occurred in 1 of 23 evaluable patients with high-grade astrocytoma, 1 of 21 with low-grade astrocytoma, and 3 of 25 with medulloblastoma/primitive neuroectodermal tumor (PNET). The CR occurred in an additional patient with medulloblastoma/PNET. No responses were observed in patients with ependymoma, brain-stem glioma, or other CNS tumors. Notably, 41% of patients with low-grade astrocytoma had SD through 12 courses. The most frequent toxicities were grade 3 or 4 neutropenia (19%) and thrombocytopenia (25%); nonhematologic toxicity was infrequent. CONCLUSIONS. Although overall objective responses were limited, further exploration of temozolomide may be warranted in children with medulloblastoma and other PNETs, or in patients with low-grade astrocytoma, perhaps in a setting of less pretreatment than the patients in the current study, or in the context of multiagent therapy. Cancer 2007;110:1542–50. � 2007 American Cancer Society.

BACKGROUND. Patients with metastatic osteosarcoma have a poor prognosis. The objectives of the study were to determine the antitumor activity and toxicity of topotecan (daily ×5) in newly diagnosed patients with metastatic osteosarcoma followed by chemotherapy (ifosfamide, carboplatin, etoposide [ICE], alternating with cisplatin and doxorubicin [CD]). METHODS. Newly diagnosed patients (≤30 years of age) with extensive metastatic disease (primary and ≥5 pulmonary nodules and/or bone metastases) with normal hepatic, renal, and cardiac function were eligible. Patients were eligible to receive further topotecan after standard chemotherapy if they exhibited a response. Twenty-eight patients were enrolled. Seventeen had metastases to the lung only and 11 had metastases to the bone or multiple sites. Of 28 patients enrolled, 27 could be evaluated for response. A limited dose escalation was incorporated. RESULTS. No responses were seen in the 11 patients treated at 3 mg/m2/day. One partial response (PR) and 1 clinical response (CLR) were reported among 15 patients who received topotecan at 3.5 mg/m2/day. No dose-limiting toxicity was observed. Principal nondose-limiting toxicities were hematologic and gastrointestinal. The 2- and 5-year event-free survival rates were low, 7% and 4%, respectively, but the 2- and 5-year overall survival rates were 44% and 22%, respectively. CONCLUSIONS. Topotecan at dose of 3.5 mg/m2/day can be safely administered upfront to newly diagnosed patients without excessive toxicity. Insufficient activity was seen with topotecan in this schedule to warrant further studies in osteosarcoma. The combination of ICE and CD was tolerable when delivered after initial topotecan therapy. Cancer 2007. © 2007 American Cancer Society.

BACKGROUND. Patients with cancer who have thrombocytopenia may experience acute coronary syndromes (ACS), and the use of aspirin (ASA) poses an increased risk of bleeding. The purpose of this study was to test the hypothesis that the benefit of ASA therapy in the treatment of ACS would extend to cancer patients with thrombocytopenia and outweigh the risks of severe bleeding. METHODS. The records of all cancer patients diagnosed with an ACS in 2001 and referred for cardiology consultation were reviewed. Patients were divided into 2 groups on the basis of platelet count, >100 cells k/μL and ≤100 cells k/μL. Data were collected on the use of ASA therapy, bleeding complications, and survival rates. The authors assessed group differences by using the Wilcoxon rank sum test or 2-tailed Fisher exact test, as appropriate. Univariate and multivariate logistic regression models were used to assess factors potentially associated with 7-day survival. RESULTS. In cancer patients with ACS and thrombocytopenia, those who did not receive ASA had a 7-day survival rate of 6% compared with 90% in those who did receive ASA (P 100 cells k/μL) who received ASA had a 7-day survival rate of 88% compared with 45% in those who did not receive ASA (P = .0096). CONCLUSIONS. Therapy with ASA was associated with a significantly improved 7-day survival after ACS in cancer patients, with or without thrombocytopenia, and not associated with more severe bleeding. Cancer 2007;109:621–627. © 2006 American Cancer Society.